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1. Targeting Serotonin With Common Antidepressants Induces Rapid Recovery From Cytopenia

Author

Guillemette Fouquet, Julien Rossignol, Nicolas Garcelon, Olivier Hermine, Francine Côté, Tereza Coman, Garcelon, Nicolas, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Sud Francilien, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), and Département d'hématologie [Gustave Roussy]

Subjects
[SDV]Life Sciences [q-bio], MESH: Hematopoiesis, Cell Biology, General Medicine, G-CSF, chemotherapy, Antidepressive Agents, Hematopoiesis, serotonin, [SDV] Life Sciences [q-bio], MESH: Serotonin Uptake Inhibitors, Mice, antidepressants, Granulocyte Colony-Stimulating Factor, autologous hematopoietic stem cell transplantation, Animals, Humans, cytopenia, MESH: Animals, MESH: Granulocyte Colony-Stimulating Factor, MESH: Serotonin, MESH: Antidepressive Agents, MESH: Mice, Selective Serotonin Reuptake Inhibitors, Developmental Biology
Abstract

The hematopoietic system uses several, yet undiscovered, factors to adapt to stresses such as chemotherapy, infections, or bleeding. Serotonin is commonly known as a neurotransmitter but is also produced and used in peripheral organs. In particular, we have shown that serotonin synthesized in the bone marrow is necessary for erythroid progenitors’ survival and proliferation. Serotonin levels can be increased by FDA approved antidepressants called selective serotonin reuptake inhibitors (SSRI). In this work, we report a previously unknown role of SSRI in the recovery of cytopenia, after autologous hematopoietic stem cell transplantation in patients and after sub-lethal irradiation in mice. We also observed an unexpected cooperation between SSRI and G-CSF on the improvement of the 3 hematopoietic lineages. Of note, SSRI do not seem to affect blood cells production in the absence of stress-induced hematopoiesis. We propose that the serotonergic system could be a valuable therapeutic target in stress-induced cytopenia, especially as a rescue after radiation or chemotherapy.

Published
2022

2. Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape

Author

Qing Li, Jieyi Chen, Pierre Faux, Miguel Eduardo Delgado, Betty Bonfante, Macarena Fuentes-Guajardo, Javier Mendoza-Revilla, J. Camilo Chacón-Duque, Malena Hurtado, Valeria Villegas, Vanessa Granja, Claudia Jaramillo, William Arias, Rodrigo Barquera, Paola Everardo-Martínez, Mirsha Sánchez-Quinto, Jorge Gómez-Valdés, Hugo Villamil-Ramírez, Caio C. Silva de Cerqueira, Tábita Hünemeier, Virginia Ramallo, Sijie Wu, Siyuan Du, Andrea Giardina, Soumya Subhra Paria, Mahfuzur Rahman Khokan, Rolando Gonzalez-José, Lavinia Schüler-Faccini, Maria-Cátira Bortolini, Victor Acuña-Alonzo, Samuel Canizales-Quinteros, Carla Gallo, Giovanni Poletti, Winston Rojas, Francisco Rothhammer, Nicolas Navarro, Sijia Wang, Kaustubh Adhikari, Andrés Ruiz-Linares, Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University [Shanghai]-Collaborative Innovation Center for Genetics and Development, CAS Key Laboratory of Computational Biology, Chinese Academy of Sciences [Beijing] (CAS)-University of Chinese Academy of Sciences [Beijing] (UCAS)-Shanghai Institute of Nutrition and Health, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), División Antropología [La Plata] (DA), Facultad de Ciencias Naturales y Museo [La Plata] (FCNyM), Universidad Nacional de la Plata [Argentine] (UNLP)-Universidad Nacional de la Plata [Argentine] (UNLP), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Departamento de Tecnología Médica, Universidad de Tarapaca, Laboratorios de Investigación y Desarrollo (LID), Universidad Peruana Cayetano Heredia (UPCH), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Division of Vertebrates and Anthropology, The Natural History Museum [London] (NHM), Laboratorio de Genética Molecular, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Molecular Genetics Laboratory, National School of Anthropology and History [Mexico City, Mexico] (NSAH), Department of Archaeogenetics [Jena] (DAG), Max Planck Institute for the Science of Human History (MPI-SHH), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Forensic Science, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Unidad de Genomica de Poblaciones Aplicada a la Salud, Scientific Police of São Paulo State [Ourinhos, Brazil], Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo = University of São Paulo (USP), Departamento de Genética, Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Instituto Patagónico de Ciencias Sociales y Humanas, School of Mathematics and Statistics [Milton Keynes], Faculty of Science, Technology, Engineering and Mathematics [Milton Keynes], The Open University [Milton Keynes] (OU)-The Open University [Milton Keynes] (OU), Facultad de Medicina & Instituto de Alta Investigacion, Universidad de Tarapaca-Universidade de Chile, Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, University College of London [London] (UCL), the National Natural Science Foundation of China (#31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), Ministry of Science and Technology of China (2020YFE0201600), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) and the 111 Project (B13016), the Leverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), Universidad de Antioquia (CODI sostenibilidad de grupos 2013- 2014 and MASO 2013-2014), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Apoio a Núcleos de Excelência Program), Fundação de Aperfeiçoamento de Pessoal de Nível Superior and the National Institute of Dental and Craniofacial Research (R01-DE027023, U01-DE020078, R01-DE016148, X01-HG007821), Santander Research & Scholarship Award. B.B. is supported by a doctoral scholarship from Ecole Doctorale 251 Aix-Marseille Université., and ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011)

Subjects
MESH: Neanderthals, MESH: Cell Differentiation, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, MESH: Nose, Medicine (miscellaneous), Sitios de Carácter Cuantitativo, Quantitative trait, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Estudio de Asociación del Genoma Completo, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Genome-Wide Association Study, MESH: Animals, General Agricultural and Biological Sciences, MESH: Mice
Abstract

e report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking of 2D portraits and testing for association with inter-landmark distances. We detected significant associations (P-value

Published
2023

3. Chromosome folding and prophage activation reveal specific genomic architecture for intestinal bacteria

Author

Lamy-Besnier, Quentin, Bignaud, Amaury, Garneau, Julian, Titecat, Marie, Conti, Devon, von Strempel, Alexandra, Monot, Marc, Stecher, Bärbel, Koszul, Romain, Debarbieux, Laurent, Marbouty, Martial, Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), German Center for Infection Research, Partnersite Munich (DZIF), This research was supported by funding to BS from DFG-STE-1971/11–1 (PhaStGut project), to BS from the European Research Council under the Horizon 2020 Program (ERC grant agreement 865615), to LD and MMa from PRCI ANR-20-CE92-0048 (PhaStGut project), and to RK from the European Research Council under the Horizon 2020 Program (ERC grant agreement 771813) and from JPI-EC-AMR STARCS ANR-16-JPEC-0003–05. QLB received funding from École Doctorale FIRE-Program Bettencourt. AB is supported by an ENS fellowship from the French Ministry of Higher Education, Research and Innovation. MMo and JRG were supported by JCJC ANR-18-CE35-0011 (project CDPhages). MT received funding from DigestScience. Biomics Platform, C2RT, Institut Pasteur, Paris, France, was supported by France Génomique (ANR-10-INBS-09) and IBISA. AB and DC belong to Ecole Doctorale Complexité du vivant ED515 of Sorbonne Université., ANR-20-CE92-0048,PhaStGut,Etude des mécanismes de la coexistence stable entre bactériophages et bactéries et de ses conséquences sur la fonction du microbiote intestinal(2020), ANR-16-JPEC-0003,STARCS,Selection and Transmission of Antimicrobial Resistance in Complex Systems(2016), ANR-18-CE35-0011,CDPhages,Le role des bactériophages dans l'évolution de la virulence chez Clostridium difficile(2018), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and European Project: 771813,ERC-2017-COG,SynarchiC(2018)

Subjects
Microbiology (medical), MESH: Humans, Virome, MESH: Genomics, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, OMM12, Phages Gut HiC Virome OMM12 3D signatures, Microbiology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Bacteria, MESH: Prophages, 3D signatures, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Phages, Gut, MESH: Animals, MESH: Ecosystem, MESH: Chromosomes, MESH: Bacteriophages, HiC, MESH: Mice
Abstract

Background Bacteria and their viruses, bacteriophages, are the most abundant entities of the gut microbiota, a complex community of microorganisms associated with human health and disease. In this ecosystem, the interactions between these two key components are still largely unknown. In particular, the impact of the gut environment on bacteria and their associated prophages is yet to be deciphered. Results To gain insight into the activity of lysogenic bacteriophages within the context of their host genomes, we performed proximity ligation-based sequencing (Hi-C) in both in vitro and in vivo conditions on the 12 bacterial strains of the OMM12 synthetic bacterial community stably associated within mice gut (gnotobiotic mouse line OMM12). High-resolution contact maps of the chromosome 3D organization of the bacterial genomes revealed a wide diversity of architectures, differences between environments, and an overall stability over time in the gut of mice. The DNA contacts pointed at 3D signatures of prophages leading to 16 of them being predicted as functional. We also identified circularization signals and observed different 3D patterns between in vitro and in vivo conditions. Concurrent virome analysis showed that 11 of these prophages produced viral particles and that OMM12 mice do not carry other intestinal viruses. Conclusions The precise identification by Hi-C of functional and active prophages within bacterial communities will unlock the study of interactions between bacteriophages and bacteria across conditions (healthy vs disease).

Published
2023

4. Evaluation of NS4A, NS4B, NS5 and 3′UTR Genetic Determinants of WNV Lineage 1 Virulence in Birds and Mammals

Author

Lise Fiacre, Steeve Lowenski, Céline Bahuon, Marine Dumarest, Bénédicte Lambrecht, Maha Dridi, Emmanuel Albina, Jennifer Richardson, Stéphan Zientara, Miguel-Ángel Jiménez-Clavero, Nathalie Pardigon, Gaëlle Gonzalez, Sylvie Lecollinet, Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sciensano [Bruxelles], Réseau International des Instituts Pasteur (RIIP), Centro de Investigacion en Sanidad Animal (INIA-CISA), Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA), CIBER de Epidemiología y Salud Pública (CIBERESP), Cellule d'Intervention Biologique d'Urgence (Centre National de Référence) - Laboratory for Urgent Response to Biological Threats (National Reference Center) (CIBU), Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), This work was supported by the European Commission (HEALTH.2020.2.3-3-3 261391 EuroWestNile project and through DG SANTé (EU-RL on equine diseases))., and European Project: 261391,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,EUROWESTNILE(2011)

Subjects
MESH: Humans, molecular determinants, [SDV]Life Sciences [q-bio], MESH: Chickens, MESH: 3' Untranslated Regions, MESH: Virulence, MESH: Mammals, virulence, reverse genetics, Infectious Diseases, Virology, MESH: Animals, MESH: Mosquito Vectors, West Nile virus, MESH: Horses, MESH: Mice, MESH: West Nile virus, MESH: West Nile Fever
Abstract

West Nile virus (WNV) is amplified in an enzootic cycle involving birds as amplifying hosts. Because they do not develop high levels of viremia, humans and horses are considered to be dead-end hosts. Mosquitoes, especially from the Culex genus, are vectors responsible for transmission between hosts. Consequently, understanding WNV epidemiology and infection requires comparative and integrated analyses in bird, mammalian, and insect hosts. So far, markers of WNV virulence have mainly been determined in mammalian model organisms (essentially mice), while data in avian models are still missing. WNV Israel 1998 (IS98) is a highly virulent strain that is closely genetically related to the strain introduced into North America in 1999, NY99 (genomic sequence homology > 99%). The latter probably entered the continent at New York City, generating the most impactful WNV outbreak ever documented in wild birds, horses, and humans. In contrast, the WNV Italy 2008 strain (IT08) induced only limited mortality in birds and mammals in Europe during the summer of 2008. To test whether genetic polymorphism between IS98 and IT08 could account for differences in disease spread and burden, we generated chimeric viruses between IS98 and IT08, focusing on the 3′ end of the genome (NS4A, NS4B, NS5, and 3′UTR regions) where most of the non-synonymous mutations were detected. In vitro and in vivo comparative analyses of parental and chimeric viruses demonstrated a role for NS4A/NS4B/5′NS5 in the decreased virulence of IT08 in SPF chickens, possibly due to the NS4B-E249D mutation. Additionally, significant differences between the highly virulent strain IS98 and the other three viruses were observed in mice, implying the existence of additional molecular determinants of virulence in mammals, such as the amino acid changes NS5-V258A, NS5-N280K, NS5-A372V, and NS5-R422K. As previously shown, our work also suggests that genetic determinants of WNV virulence can be host-dependent.

Published
2023

5. IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Author

Josephine Kemna, Evelyne Gout, Leon Daniau, Jessica Lao, Kristoffer Weißert, Sandra Ammann, Ralf Kühn, Matthias Richter, Christine Molenda, Anje Sporbert, Dario Zocholl, Robert Klopfleisch, Hugues Lortat-Jacob, Peter Aichele, Thomas Kammertoens, Thomas Blankenstein, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany, Institute for Immunodeficiency, Fakultät für Biologie = Faculty of Biology [Freiburg], Albert-Ludwigs-Universität Freiburg, Center of Chronic Immunodeficiency, University Medical Center and University of Freiburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], and Institute of Veterinary Pathology

Subjects
MESH: Signal Transduction, MESH: Cytokines, Cancer Research, MESH: Interferon-gamma, [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy, MESH: Animals, MESH: Neoplasms, MESH: Extracellular Matrix, Technology Platforms, MESH: Mice
Abstract

Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγΔKRKR) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγΔKRKR mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation.

Published
2023

6. Transcranial direct current stimulation (tDCS) reduces motivation to drink ethanol and reacquisition of ethanol self-administration in female mice

Author

Pedron, Solene, Dumontoy, Stephanie, Gonzalez-Marin, Maria Del Carmen, Coune, Fabien, Van Schuerbeek, Andries, Haffen, Emmanuel, Naassïla, Mickaël, Van Waes, Vincent, Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481) (NEURO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoires de neurosciences intégratives et cliniques (EA 481), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vrije Universiteit Brussel (VUB), Fondation FondaMental [Créteil], haffen, emmanuel, and Laboratoire de recherches Intégratives en Neurosciences et Psychologie Cognitive (LINC)

Subjects
MESH: Ethanol, Alcohol Drinking, [SDV]Life Sciences [q-bio], Science, MESH: Motivation, Drug-Seeking Behavior, MESH: Conditioning, Operant, Self Administration, Transcranial Direct Current Stimulation, Article, Extinction, Psychological, Mice, Reward, MESH: Behavior, Animal, Animals, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, MESH: Drug-Seeking Behavior, Motivation, Behavior, Animal, Ethanol, MESH: Transcranial Direct Current Stimulation, MESH: Extinction, Psychological, MESH: Models, Animal, Preclinical research, Models, Animal, Conditioning, Operant, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, MESH: Female, MESH: Alcohol Drinking, MESH: Self Administration, Neuroscience
Abstract

International audience; Abstract Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on “liking” (hedonic aspect; no effect in the CPP) and “wanting” (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.

Published
2022

7. In vitro cellular reprogramming to model gonad development and its disorders

Author

Gonen, Nitzan, Eozenou, Caroline, Mitter, Richard, Elzaiat, Maëva, Stévant, Isabelle, Aviram, Rona, Bernardo, Andreia Sofia, Chervova, Almira, Wankanit, Somboon, Frachon, Emmanuel, Commere, Pierre-Henri, Brailly-Tabard, Sylvie, Valon, Léo, Barrio Cano, Laura, Levayer, Romain, Mazen, Inas, Gobaa, Samy, Smith, James C., McElreavey, Kenneth, Lovell-Badge, Robin, Bashamboo, Anu, Bar-Ilan University [Israël], The Francis Crick Institute [London], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imperial College London, Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris] (IP), Biomatériaux et Microfluidiques (plateforme) - Biomaterials and Microfluidics (platform), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Mort cellulaire et homéostasie des épithéliums / Cell death and epithelial homeostasis, National Research Center [Caire, Egypte], This work is funded in part by a research grant (40000767) from the European Society of Pediatric Endocrinology (to A.B.) and by the Agence Nationale de la Recherche (ANR, ANR-10-LABX-73 REVIVE, ANR-17-CE14-0038-01, and ANR 20CE14 0007 to K.M., and ANR-19-CE14-0022 and ANR-19-CE14-0012 to A.B.). N.G., A.S.B., R.M., J.C.S., and R.L.-B. were funded by the Francis Crick Institute. The Francis Crick Institute receives its core funding from Cancer Research UK (CC2116), the UK Medical Research Council (CC2116), and the Wellcome Trust (CC2116). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. . N.G., I.S., and R.A. are funded by the ERC Starting Grant EnhanceSex (101039928). A.S.B. was also funded by the British Heart Foundation (BHF-FS/12/37/29516) and the Wellcome Trust (210987/Z/18/Z)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-17-CE14-0038,MGonDev,Etude des mécanismes du développement des gonades chez l'homme(2017), ANR-20-CE14-0007,Goldilocks,Analyse intégrée du rôle du facteur de transcription SF-1 / NR5A1 et de ses gènes cibles dépendants du dosage dans la fonction gonadique et les troubles du développement sexuel (DSD)(2020), ANR-19-CE14-0022,SexDiff,Régulation de la détermination du sexe et de la différenciation ovarienne : implications dans les troubles du développement sexuel(2019), and ANR-19-CE14-0012,RNA-SEX,Fonction de l'ARN hélicase dans la détermination du sexe chez les vertébrés et les troubles du développement du sexe chez l'homme (DSD)(2019)

Subjects
Model organisms, Chemical Biology & High Throughput, Multidisciplinary, MESH: Humans, FOS: Clinical medicine, Stem Cells, [SDV]Life Sciences [q-bio], Genome Integrity & Repair, Neurosciences, Gene Expression, MESH: Gonadal Dysgenesis, 46,XY, Tumour Biology, MESH: Induced Pluripotent Stem Cells, MESH: Cellular Reprogramming, MESH: Male, Signalling & Oncogenes, MESH: Gonads, MESH: Animals, Genetics & Genomics, MESH: Mice, MESH: Female, Developmental Biology, Computational & Systems Biology
Abstract

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro–derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9–mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.

Published
2023

8. Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis

Author

Marchal-Duval, Emmeline, Homps-Legrand, Méline, Froidure, Antoine, Jaillet, Madeleine, Ghanem, Mada, Lou, Deneuville, Justet, Aurélien, Maurac, Arnaud, Vadel, Aurelie, Fortas, Emilie, Cazes, Aurelie, Joannes, Audrey, Giersh, Laura, Mal, Herve, Mordant, Pierre, Piolot, Tristan, Truchin, Marin, Mounier, Carine, Schirduan, Ksenija, Korfei, Martina, Gunther, Andreas, Mari, Bernard, Jaschinski, Frank, Crestani, Bruno, Mailleux, Arnaud, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche sur les relations matrice extracellulaire-cellules (ERRMECe), Fédération INSTITUT DES MATÉRIAUX DE CERGY-PONTOISE (I-MAT), CY Cergy Paris Université (CY)-CY Cergy Paris Université (CY), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Justus-Liebig-Universität Gießen = Justus Liebig University (JLU)

Subjects
MESH: Idiopathic Pulmonary Fibrosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, lung, Mice, Transforming Growth Factor beta, MESH: Cell Proliferation, fibroblasts, transcription factors, MESH: Homeodomain Proteins, cell biology, Animals, Humans, MESH: Animals, human, MESH: Mice, MESH: Transforming Growth Factor beta, mouse, Cell Proliferation, Homeodomain Proteins, MESH: Humans, fibrosis, MESH: Transcription Factors, TGF beta pathway, Idiopathic Pulmonary Fibrosis, Protein Phosphatase 2C, MESH: Protein Phosphatase 2C
Abstract

Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR-dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis.

Published
2023

9. WHIM Syndrome-linked CXCR4 mutations drive osteoporosis

Author

Adrienne Anginot, Julie Nguyen, Zeina Abou Nader, Vincent Rondeau, Amélie Bonaud, Maria Kalogeraki, Antoine Boutin, Julia P. Lemos, Valeria Bisio, Joyce Koenen, Lea Hanna Doumit Sakr, Amandine Picart, Amélie Coudert, Sylvain Provot, Nicolas Dulphy, Michel Aurrand-Lions, Stéphane J. C. Mancini, Gwendal Lazennec, David H. McDermott, Fabien Guidez, Claudine Blin-Wakkach, Philip M. Murphy, Martine Cohen-Solal, Marion Espéli, Matthieu Rouleau, Karl Balabanian, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Inflammation, microbiome, immunosurveillance (MI2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of Amsterdam [Amsterdam] (UvA), Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), and Génétique et pathologies moléculaires (GPM)

Subjects
Multidisciplinary, MESH: Mutation, MESH: Humans, MESH: Immunologic Deficiency Syndromes, General Physics and Astronomy, chemokines, General Chemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], osteoporosis, General Biochemistry, Genetics and Molecular Biology, MESH: Receptors, CXCR4, MESH: Animals, CXCR4 receptor, MESH: Primary Immunodeficiency Diseases, MESH: Osteogenesis, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Osteoporosis
Abstract

WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers. Mechanistically, impaired CXCR4 desensitization disrupts cell cycle progression and osteogenic commitment of skeletal stromal/stem cells, while increasing their pro-osteoclastogenic capacities. Impaired osteogenic differentiation is evidenced in primary bone marrow stromal cells from WHIM patients. In mice, chronic treatment with the CXCR4 antagonist AMD3100 normalizes in vitro osteogenic fate of mutant skeletal stromal/stem cells and reverses in vivo the loss of skeletal cells, demonstrating that proper CXCR4 desensitization is required for the osteogenic specification of skeletal stromal/stem cells. Our study provides mechanistic insights into how CXCR4 signaling regulates the osteogenic fate of skeletal cells and the balance between bone formation and resorption.

Published
2023

10. 99mTc-NTP 15-5 is a companion radiotracer for assessing joint functional response to sprifermin (rhFGF-18) in a murine osteoarthritis model

Author

Arnaud Briat, Claire Jacques, Mélodie Malige, Laure Sudre, Geoffroy Nourissat, Philippe Auzeloux, Hans Guehring, Florent Cachin, Francis Berenbaum, Elisabeth Miot-Noirault, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), clinique des Maussins, Merck KGaA [Darmstadt, Germany], Merck & Co. Inc, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique Maussins Nollet - Ramsay (FRANCE), JESUS, MARJORIE, Pathologies articulaires associées aux maladies métaboliques et à l’âge [CRSA], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Multidisciplinary, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV]Life Sciences [q-bio], MESH: Indicators and Reagents, MESH: Quaternary Ammonium Compounds, MESH: Osteoarthritis, MESH: Heterocyclic Compounds, 1-Ring, MESH: Proteoglycans, MESH: Cartilage, Articular, MESH: Animals, MESH: Disease Models, Animal, MESH: Mice, MESH: Fibroblast Growth Factors
Abstract

With the emergence of disease modifying osteoarthritis drugs (DMOAD), imaging methods to quantitatively demonstrate their efficacy and to monitor osteoarthritis progression at the functional level are urgently needed. Our group showed that articular cartilage can be quantitatively assessed in nuclear medicine imaging by our radiotracer 99mTc-NTP 15-5 targeting cartilage proteoglycans. In this work, surgically induced DMM mice were treated with sprifermin or saline. We investigated cartilage remodelling in the mice knees by 99mTc-NTP 15-5 SPECT-CT imaging over 24 weeks after surgery, as wells as proteoglycan biochemical assays. OA alterations were scored by histology according to OARSI guidelines. A specific accumulation of 99mTc-NTP 15-5 in cartilage joints was evidenced in vivo by SPECT-CT imaging as early as 30 min post-iv injection. In DMM, 99mTc-NTP 15-5 accumulation in cartilage within the operated joints, relative to contralateral ones, was observed to initially increase then decrease as pathology progressed. Under sprifermin, 99mTc-NTP 15-5 uptake in pathological knees was significantly increased compared to controls, at 7-, 12- and 24-weeks, and consistent with proteoglycan increase measured 5 weeks post-surgery, as a sign of cartilage matrix remodelling. Our work highlights the potential of 99mTc-NTP 15-5 as an imaging-based companion to monitor cartilage remodelling in OA and DMOAD response.

Published
2022

11. Multicellular tumor spheroids of LNCaP-Luc prostate cancer cells as in vitro screening models for cytotoxic drugs

Author

Anthime Flaus, Vincent Habouzit, Nicolas de Leiris, Jean-Philippe Vuillez, Marie-Thérèse Leccia, Mathilde Simonson, Jean-Luc Perrot, Florent Cachin, Nathalie Prevot, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université Grenoble Alpes (UGA), Radiopharmaceutiques Biocliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), and Université d'Auvergne - Clermont-Ferrand I (UdA)

Subjects
B16 melanoma tumor, [SDV]Life Sciences [q-bio], Clinical Biochemistry, MESH: Epigenome, [SDV.CAN]Life Sciences [q-bio]/Cancer, high-resolution magic angle spinning, global methylome, 18F-FDG PET, radiomics, machine-learning, immunotherapy, melanoma, prediction, 2D 1H−13C NMR spectroscopy, MESH: Animals, MESH: Metabolomics, MESH: Mice, MESH: Vitamin U, Prostate cancer, hypoxia, B16 melanoma cell culture, metabolomics, MESH: Melanoma, Experimental, spheroid, MESH: Methionine, orthogonal partial least squares discriminant analysis, l-[13C-methyl]methionine, methyl metabolism
Abstract

International audience; An increasing number of studies concerning solid cancers, including prostate cancer, are tending to demonstrate the predominant role of the interactions of tumor cells with their microenvironment, and underlining the relevance of therapeutic approaches co-targeting these two components. Artificial in vitro 3D culture models, such as spheroids, are therefore being designed to allow intercellular interactions between tumor cells and the matrix, under hypoxic conditions mimicking a microtumor. This project aims to develop and characterize a multicellular tumor spheroid (MCTS) model of human prostate cancer cells expressing PSMA, for in vitro drug screening. To this end, 1,000 cells/well were seeded in 100 µl of culture medium with 0.5% of methylcellulose in 96-well, non-adherent, V-shaped bottom plates. Bioluminescent imaging of the spheroids enabled the measurement of spheroid growth. From Day 7 of growth, immunofluorescence studies showed cellular proliferation (Ki-67), mainly located in the periphery of the spheroid section, associated with the formation of an apoptotic core (TUNEL). Scanning electron microscopy and fluorescent imaging (Lox-1 probe) showed the presence of an extracellular matrix and the installation of an oxygen gradient leading to the formation of a hypoxic area during growth. This hypoxia was correlated with increased VEGF excretion. Drug sensitivity was assessed on 2D and 3D cultures. The LNCaP-Luc spheroids are more resistant to docetaxel and TH-302, a hypoxia-activated prodrug, compared with cells grown in a monolayer. For docetaxel, this resistance increased with the spheroid growth stage, whereas the activity of TH-302 was potentiated by the hypoxic environment. In conclusion, the development of LNCaP-Luc cell MCTS provides a simple model mimicking a microtumor; it appears to be particularly well-suited to the validation of new therapeutic approaches targeting proliferation and the microenvironment.

Published
2022

12. TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks

Author

Alexandre Nore, Ariadna B. Juarez-Martinez, Julie Clément, Christine Brun, Boubou Diagouraga, Hamida Laroussi, Corinne Grey, Henri Marc Bourbon, Jan Kadlec, Thomas Robert, Bernard de Massy, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Clement, Julie, Thomas, Frank, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université Grenoble Alpes (UGA)

Subjects
Male, Spo11, Catalytic complex, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], Mutant, MESH: DNA Breaks, Double-Stranded, General Physics and Astronomy, MESH: Spermatocytes, General Biochemistry, Genetics and Molecular Biology, Chromosomes, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, chemistry.chemical_compound, Mice, Meiosis, Spermatocytes, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, DNA Breaks, Double-Stranded, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis, Double strand, [SDV.BDD.GAM] Life Sciences [q-bio]/Development Biology/Gametogenesis, Autosome, Multidisciplinary, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Point mutation, fungi, MESH: DNA, General Chemistry, DNA, MESH: Meiosis / genetics, MESH: Male, Cell biology, MESH: Meiosis, biology.protein, Female, MESH: Chromosomes, MESH: Female
Abstract

Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. In male and female meiotic cells, DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identified their conserved interacting domains by structural analysis. We then analysed the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity was strongly reduced genome-wide in oocytes, but only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity was delayed in autosomes. These results provide evidence that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity by integrating specific chromosomal features.

Published
2022

13. Awake perception is associated with dedicated neuronal assemblies in the cerebral cortex

Author

Anton Filipchuk, Joanna Schwenkgrub, Alain Destexhe, Brice Bathellier, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Funding was provided by the European Community, Future and Emerging Technologies program—Human Brain Project (no. H2020-945539 to A.D.), Paris-Saclay University ‘Initiatives de Recherches Stratégiques’—NeuroSaclay and Icode (to B.B. and A.D.), Agence Nationale pour la Recherche (no. 12-PDOC-0006 to B.B., PARADOX to A.D.), Région Ile de France—DIM Cerveau Pensée—MULTISENSE (to B.B.), Fondation pour l’Audition (nos. FPA IDA02 and APA 2016-03 to B.B.), and the European Research Council (no. CoG 770841 DEEPEN to B.B.). B.B. thanks the Fondation pour l’Audition for their support to the Institut de l’Audition., ANR-12-PDOC-0006,SENSEMAKER,Traitement cortical multisensoriel et émergence de percepts supra-modaux(2012), ANR-17-CE16-0024,PARADOX,Le sommeil paradoxical décodé(2017), European Project: 945539,H2020,H2020-SGA-FETFLAG-HBP-2019,HBP SGA3(2020), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), PERIGNON, Alain, Retour Post-Doctorant - Traitement cortical multisensoriel et émergence de percepts supra-modaux - - SENSEMAKER2012 - ANR-12-PDOC-0006 - PDOC - VALID, Le sommeil paradoxical décodé - - PARADOX2017 - ANR-17-CE16-0024 - AAPG2017 - VALID, and Human Brain Project Specific Grant Agreement 3 - HBP SGA3 - - H20202020-01-01 - 2023-09-30 - 945539 - VALID

Subjects
Auditory Cortex, Neurons, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, General Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Acoustic Stimulation, MESH: Neurons, MESH: Anesthetics, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Perception, Mice, MESH: Auditory Perception, MESH: Wakefulness, Acoustic Stimulation, Auditory Perception, Animals, Perception, MESH: Animals, MESH: Auditory Cortex, Wakefulness, MESH: Mice, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Anesthetics
Abstract

Neural activity in the sensory cortex combines stimulus responses and ongoing activity, but it remains unclear whether these reflect the same underlying dynamics or separate processes. In the present study, we show in mice that, during wakefulness, the neuronal assemblies evoked by sounds in the auditory cortex and thalamus are specific to the stimulus and distinct from the assemblies observed in ongoing activity. By contrast, under three different anesthetics, evoked assemblies are indistinguishable from ongoing assemblies in the cortex. However, they remain distinct in the thalamus. A strong remapping of sensory responses accompanies this dynamic state change produced by anesthesia. Together, these results show that the awake cortex engages dedicated neuronal assemblies in response to sensory inputs, which we suggest is a network correlate of sensory perception.

Published
2022

14. Protective role of host complement system in Aspergillus fumigatus infection

Author

Rajashri Shende, Sarah Sze Wah Wong, Heikrujam Thoihen Meitei, Girdhari Lal, Taruna Madan, Vishukumar Aimanianda, Jayanta Kumar Pal, Arvind Sahu, Savitribai Phule Pune University [India], Dr. D. Y. Patil Vidyapeeth [Pune] (DPU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Département de Mycologie - Department of Mycology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), National Institute for Research in Reproductive and Child Health [Mumbai] (NIRRCH), AS is a J.C. Bose National Fellow. His lab is supported by the Department of Biotechnology, India, Project Grant BT/PR28506/MED/29/1307/2018. VA was supported by FUNHYDRO (ANR-16S-CE110020-01) and FUNPOLYVAC (ANR-21-CE17-0032) grants. SW was supported by Pasteur-Roux-Cantarini postdoctoral fellowship., ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016), and ANR-21-CE17-0032,FUNPOLYVAC,Explorer les polysaccharides fongiques de la paroi cellulaire pour les immunothérapies(2021)

Subjects
Aspergillus fumigatus, infectious disease, Immunology, MESH: Complement Factor B, MESH: Spores, Fungal, MESH: Complement C5, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Animals, MESH: Lung, MESH: Aspergillosis, MESH: Aspergillus fumigatus, innate immunity, MESH: Mice, complement system, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, systemic aspergillosis
Abstract

Invasive aspergillosis (IA) is a life-threatening fungal infection for immunocompromised hosts. It is, therefore, necessary to understand the immune pathways that control this infection. Although the primary infection site is the lungs, aspergillosis can disseminate to other organs through unknown mechanisms. Herein we have examined thein vivorole of various complement pathways as well as the complement receptors C3aR and C5aR1 during experimental systemic infection byAspergillus fumigatus, the main species responsible for IA. We show that C3 knockout (C3-/-) mice are highly susceptible to systemic infection ofA. fumigatus. Intriguingly, C4-/-and factor B (FB)-/-mice showed susceptibility similar to the wild-type mice, suggesting that either the complement pathways display functional redundancy during infection (i.e., one pathway compensates for the loss of the other), or complement is activated non-canonically byA. fumigatusprotease. Ourin vitrostudy substantiates the presence of C3 and C5 cleaving proteases inA. fumigatus. Examination of the importance of the terminal complement pathway employing C5-/-and C5aR1-/-mice reveals that it plays a vital role in the conidial clearance. This, in part, is due to the increased conidial uptake by phagocytes. Together, our data suggest that the complement deficiency enhances the susceptibility to systemic infection byA. fumigatus.

Published
2022

15. Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota That Protects From Metabolic Diseases

Author

Emelyne Lécuyer, Emmanuel Gautier, Nathalie Kapel, Moez Rhimi, Amélie Lacombe, Benoit Chassaing, Michèle Garlatti, Emmanuelle Maguin, Magali Fradet, Philippe Gérard, Philippe Lesnik, Tiphaine Le Roy, Samira Boudebbouze, Farid Ichou, Maharajah Ponnaiah, Thierry Huby, Aurélie Gestin, Nicolas Venteclef, Catherine Philippe, Jean-Baptiste Huré, Microbiota Interaction with Human and Animal (MIHA), Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunité et métabolisme dans le diabète = IMmunity and MEtabolism in DIABetes [CRC] (IMMEDIAB Lab), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Georgia State University, University System of Georgia (USG), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Gautier, Emmanuel, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Coprologie Fonctionnelle [Pitié-Salpêtrière], Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Department of Computer Science, Atlanta (Georgia State University), University System of Georgia (USG)-University System of Georgia (USG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This study was supported by INSERM, Sorbonne Université, the Fondation de France (00029519), and the Institute of Cardiometabolism and Nutrition (IHU-ICAN, ANR-10-IAHU-05). E.L. was supported by the Fondation Lefoulon Delalande/Institut de France and the Région Ile-de-France CORDDIM., ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
MESH: Inflammation, Male, Genetically modified mouse, MESH: Mice, Transgenic, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, MESH: Metabolic Diseases, Mice, Transgenic, Inflammation, Context (language use), Biology, Gut flora, Diet, High-Fat, MESH: Gastrointestinal Microbiome, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Metabolic Diseases, Internal Medicine, medicine, MESH: Obesity, Animals, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, MESH: Mice, Barrier function, 030304 developmental biology, 0303 health sciences, MESH: Dendritic Cells, Immunogenicity, Dendritic Cells, biology.organism_classification, Acquired immune system, MESH: Male, Gastrointestinal Microbiome, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Diet, High-Fat, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Immunology, Immunology and Transplantation, medicine.symptom, 030215 immunology
Abstract

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes.The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet.Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses.Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

Published
2021

16. Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Author

Mohamed A. Abu el Maaty, Julie Terzic, Céline Keime, Daniela Rovito, Régis Lutzing, Darya Yanushko, Maxime Parisotto, Elise Grelet, Izzie Jacques Namer, Véronique Lindner, Gilles Laverny, Daniel Metzger, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), metzger, daniel, ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), and ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010)

Subjects
Male, Prostatic Intraepithelial Neoplasia, Multidisciplinary, MESH: Humans, MESH: Prostatic Intraepithelial Neoplasia, [SDV]Life Sciences [q-bio], Cell Plasticity, Prostatic Neoplasms, MESH: Cell Plasticity, Hypoxia-Inducible Factor 1, alpha Subunit, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, MESH: Male, [SDV] Life Sciences [q-bio], Mice, MESH: Hypoxia, MESH: Prostatic Neoplasms, Disease Progression, Animals, Humans, MESH: Animals, MESH: Disease Progression, Hypoxia, MESH: Mice
Abstract

Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten (i)pe−/− mice that recapitulate prostate carcinogenesis in humans. We found that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, thus enhancing malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity, leading to the emergence of cells that overexpress Transglutaminase 2 (TGM2) and have impaired androgen signaling. Elevated TGM2 levels in patients with PCa are associated with shortened progression-free survival after prostatectomy. Last, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.

Published
2022

17. A long noncoding RNA influences the choice of the X chromosome to be inactivated

Author

Andreas Hierholzer, Corinne Chureau, Alessandra Liverziani, Nerea Blanes Ruiz, Bruce M. Cattanach, Alexander N. Young, Manish Kumar, Andrea Cerase, Phil Avner, European Molecular Biology Laboratory [Rome] (EMBL), Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrates Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Queen Mary University of London (QMUL), and MRC Harwell Institute [UK]

Subjects
X Chromosome, [SDV]Life Sciences [q-bio], female mouse embryo, noncoding RNA, MESH: Mammals, Mice, pluripotency factors, Genetic, X Chromosome Inactivation, Dosage Compensation, Genetic, Animals, MESH: Animals, MESH: Mice, Alleles, Mammals, MESH: X Chromosome Inactivation, Multidisciplinary, MESH: Alleles, MESH: Dosage Compensation, Genetic, MESH: RNA, Long Noncoding, X chromosome inactivation, X-controlling element, Female, RNA, Long Noncoding, Dosage Compensation, RNA, Long Noncoding, MESH: Female
Abstract

X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element ( Xce ). Although the Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong Xce alleles we show that Lppnx modulates the expression of Xist lncRNA , one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of Xist . This effect is counteracted by enhanced binding of Rex1 in DxPas34 , another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong Xce alleles results from differential transcription factor binding of Xist Intron 1 and DxPas34 , and that Lppnx represents a decisive factor in explaining the action of the Xce .

Published
2022

18. The Transcription Coregulator RIP140 Inhibits Cancer Cell Proliferation by Targeting the Pentose Phosphate Pathway

Author

Valentin Jacquier, Delphine Gitenay, Vincent Cavaillès, Catherine Teyssier, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Herrada, Anthony

Subjects
MESH: Glucosephosphate Dehydrogenase, pentose phosphate pathway, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glucosephosphate Dehydrogenase, Catalysis, Inorganic Chemistry, Mice, breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], G6PD, transcription, RIP140, Animals, MESH: Animals, MESH: Neoplasms, Physical and Theoretical Chemistry, Molecular Biology, MESH: Mice, Spectroscopy, MESH: Pentose Phosphate Pathway, Cell Proliferation, Organic Chemistry, General Medicine, Fibroblasts, Computer Science Applications, MESH: Glucose, Glucose, MESH: Fibroblasts, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract

International audience; Cancer cells switch their metabolism toward glucose metabolism to sustain their uncontrolled proliferation. Consequently, glycolytic intermediates are diverted into the pentose phosphate pathway (PPP) to produce macromolecules necessary for cell growth. The transcription regulator RIP140 controls glucose metabolism in tumor cells, but its role in cancer-associated reprogramming of cell metabolism remains poorly understood. Here, we show that, in human breast cancer cells and mouse embryonic fibroblasts, RIP140 inhibits the expression of the gene-encoding G6PD, the first enzyme of the PPP. RIP140 deficiency increases G6PD activity as well as the level of NADPH, a reducing cofactor essential for macromolecule synthesis. Moreover, G6PD knock-down inhibits the gain of proliferation observed when RIP140 expression is reduced. Importantly, RIP140-deficient cells are more sensitive to G6PD inhibition in cell proliferation assays and tumor growth experiments. Altogether, this study describes a novel role for RIP140 in regulating G6PD levels, which links its effect on breast cancer cell proliferation to metabolic rewiring.

Published
2022
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19. Reduction in sound discrimination in noise is related to envelope similarity and not to a decrease in envelope tracking abilities

Author

Samira Souffi, Léo Varnet, Meryem Zaidi, Brice Bathellier, Chloé Huetz, Jean‐Marc Edeline, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire des systèmes perceptifs (LSP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), JME was supported by grants from the French Agence Nationale de la Recherche (ANR) (ANR-14-CE30-0019-01). SS was supported by the Fondation pour la Recherche Médicale (FRM) grant number ECO20160736099 and by the Entendre Foundation., ANR-14-CE30-0019,HEART,Ecouter le temps(2014), Edeline, Jean-Marc, and Appel à projets générique - Ecouter le temps - - HEART2014 - ANR-14-CE30-0019 - Appel à projets générique - VALID

Subjects
Auditory Cortex, MESH: Humans, Physiology, [SDV]Life Sciences [q-bio], Guinea Pigs, MESH: Acoustic Stimulation, MESH: Sound, Temporal envelope tracking, MESH: Noise, MESH: Guinea Pigs, [SDV] Life Sciences [q-bio], Degraded acoustic conditions, Mice, Sound, Acoustic Stimulation, Auditory Perception, Auditory system, Humans, Animals, MESH: Animals, Neuronal and behavioral discrimination, Noise, MESH: Mice
Abstract

International audience; Key points: In quiet, envelope tracking in the low amplitude modulation range (

Published
2022

20. SNORD116 and growth hormone therapy impact IGFBP7 in Prader–Willi syndrome

Author

Lisa Cole Burnett, Françoise Conte Auriol, Eric Bieth, Jean Pierre Salles, Juliette Salles, Maithé Tauber, Gwenaelle Diene, Catherine Molinas, Rudolph L. Leibel, Boris V. Skryabin, Isabelle Gennero, Timofey S. Rozhdestvensky, Sanaa Eddiry, Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence du Syndrome de Prader-Willi, Pôle Enfants [CHU Toulouse], Service Psychiatrie et psychologie médicale [CHU Toulouse], Pôle Psychiatrie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Illinois [Chicago] (UIC), University of Illinois System, Columbia University [New York], and Pistre, Karine

Subjects
0301 basic medicine, MESH: Prader-Willi Syndrome* / genetics, medicine.medical_specialty, MESH: RNA, Small Nucleolar, congenital, hereditary, and neonatal diseases and abnormalities, IGFBP7, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, MESH: Neurons, MESH: Induced Pluripotent Stem Cells, Article, MESH: Prader-Willi Syndrome* / drug therapy, 03 medical and health sciences, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Downregulation and upregulation, Internal medicine, medicine, Animals, Humans, RNA, Small Nucleolar, MESH: Animals, MESH: Mice, Genetics (clinical), Neurons, MESH: Humans, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Dopaminergic, nutritional and metabolic diseases, medicine.disease, Phenotype, Pathophysiology, nervous system diseases, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, MESH: Growth Hormone, Growth Hormone, Knockout mouse, business, Genomic imprinting, Prader-Willi Syndrome, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Purpose: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS.Methods: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness.Results: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1.Conclusion: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.

Published
2021

21. A novel microduplication in <scp> INPP5A </scp> segregates with schizophrenia spectrum disorder in the family of a patient with both childhood onset schizophrenia and autism spectrum disorder

Author

Małgorzata Drozd, Maria Capovilla, Florence Askenazy, Susanne Thümmler, Arnaud Fernandez, Barbara Bardoni, Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, inositol pathway, INPP5A, MESH: Pedigree, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, CNV, Central nervous system, Dendritic spine morphogenesis, 030105 genetics & heredity, MESH: Phenotype, behavioral disciplines and activities, MESH: Child Development Disorders, Pervasive, MESH: Brain, 03 medical and health sciences, Neurodevelopmental disorder, MESH: Child, mental disorders, Gene duplication, Genetics, medicine, MESH: Animals, childhood-onset schizophrenia, MESH: Inositol Polyphosphate 5-Phosphatases, MESH: Mice, Gene, Genetics (clinical), MESH: Adolescent, MESH: Autism Spectrum Disorder, MESH: Humans, business.industry, MESH: Genetic Predisposition to Disease, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Adult, medicine.disease, neurodevelopmental disorder, MESH: Male, Pathophysiology, MESH: Siblings, 030104 developmental biology, medicine.anatomical_structure, MESH: Young Adult, Autism spectrum disorder, Schizophrenia, MESH: Disease Models, Animal, business, MESH: Female, MESH: Schizophrenia, Childhood
Abstract

Childhood-Onset Schizophrenia (COS) is a very rare and severe psychiatric disorder defined by adult schizophrenia symptoms occurring before the age of 13. We report a microduplication in the 10q26.3 region including part of the Inositol Polyphosphate-5-Phosphatase A (INPP5A) gene that segregates with Schizophrenia Spectrum Disorders (SSDs) in the family of a female patient affected by both COS and Autism Spectrum Disorder (ASD). Phenotyping and genotyping (including CGH-array) were performed for mother, healthy sister, and affected child according to the GenAuDiss protocol (NCT02565524). The duplication size is 324 kb and is present in a patient with COS and in her mother with SSD, but not in the patient's healthy sister. INPP5A encodes a membrane-associated 43 kDa type I inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. This protein is found both in mouse and human brains and we found that its Drosophila homologue 5PtaseI is specifically expressed in the central nervous system. Hydrolyzed products from InsP3 5-phosphatases mobilize intracellular calcium, which is relevant for dendritic spine morphogenesis in neurons and altered in both schizophrenia and ASD. These may constitute arguments in favor of this gene alteration in the pathophysiology of COS.

Published
2021

22. Linking microbiota composition with antimalarial antibody response

Author

Liliana Mancio-Silva, Mathilde Gendrin, Ottavia Romoli, Microbiote des insectes vecteurs / Microbiota of Insect Vectors [Cayenne, Guyane française], Vectopôle Amazonien Emile Abonnenc [Cayenne, Guyane française], Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Parasites et Insectes vecteurs - Department of Parasites and Insect Vectors, Institut Pasteur [Paris] (IP), This work is funded by the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX-62-IBEID) and by ANR JCJC MosMi to M.G. (grant no. ANR-18-CE15-0007)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-18-CE15-0007,MosMi,Remodelage du microbiote de moustique pour étudier son impact sur la transmission du paludisme(2018)

Subjects
0106 biological sciences, Plasmodium, MESH: Parasitemia, 2019-20 coronavirus outbreak, MESH: Malaria, malaria, severity, Spleen, Parasitemia, Biology, digestive system, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, fluids and secretions, parasitic diseases, microbiota, medicine, MESH: Microbiota, MESH: Animals, MESH: Mice, 030304 developmental biology, 0303 health sciences, Germinal center, medicine.disease, biology.organism_classification, MESH: Antimalarials, Virology, MESH: Antibody Formation, 3. Good health, stomatognathic diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, medicine.anatomical_structure, Antibody response, Parasitology, Malaria, Microbiota composition
Abstract

International audience; Microbiota composition recently arose as a factor correlating with malaria infection. Mandal et al. showed, via cecal transplant and antibacterial treatment, that the mouse microbiota modulates parasitemia by affecting spleen germinal centers where B cells are matured. They further identified correlations between microbiota composition and malaria severity in Ugandan children.

Published
2021

23. Rare missense variant inMSH4associated with primary gonadal failure in both 46, XX and 46, XY individuals

Author

Mehdi Totonchi, Mehri Mashayekhi, Ken McElreavey, Navid Almadani, Anu Bashambou, Arvand Akbari, Kimiya Padidar, Najmeh Salehi, Mohammad Ali Sadighi Gilani, Royan Institute for Reproductive Biomedicine [Tehran, Iran], Academic Center for Education, Culture and Research (ACECR), University of Tehran, Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This study was financially supported by Royan Institute, Tehran, Iran, and Institut Pasteur, Paris, France, We are sincerely thankful to the personnel of Royan Department of Genetics and the Human Developmental Genetics Unit of Institut Pasteur, Paris, France, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Proband, 46, XX Disorders of Sex Development, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Iran, MESH: Mice, Knockout, Mice, non-obstructive azoospermia, Missense mutation, MESH: Animals, Exome sequencing, Mice, Knockout, Sanger sequencing, Genetics, 0303 health sciences, MESH: Paris, 030305 genetics & heredity, Rehabilitation, Obstetrics and Gynecology, oligozoospermia, DNA-Binding Proteins, symbols, Female, primary gonadal failure, France, Paris, dbSNP, familial exome sequencing, Biology, 03 medical and health sciences, symbols.namesake, MESH: Cell Cycle Proteins, Animals, Humans, MESH: Mice, Gene, Retrospective Studies, 030304 developmental biology, Disorder of Sex Development, 46,XY, MESH: Humans, MESH: Retrospective Studies, MSH4, MESH: Male, primary ovarian insufficiency, MESH: France, MSH5, Reproductive Medicine, MESH: Iran, MESH: Female, MESH: DNA-Binding Proteins
Abstract

STUDY QUESTIONCan whole-exome sequencing (WES) reveal a shared pathogenic variant responsible for primary gonadal failure in both male and female patients from a consanguineous family?SUMMARY ANSWERPatients with primary ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) were homozygous for the rare missense variant p. S754L located in the highly conserved MSH4 MutS signature motif of the ATPase domain. An oligozoospermic patient was heterozygous for the variant.WHAT IS KNOWN ALREADYMSH4 is a meiosis-specific protein expressed at a certain level in the testes and ovaries. Along with its heterodimer partner MSH5, it is responsible for double-strand Holliday junction recognition and stabilization, to ensure accurate chromosome segregation during meiosis. Knockout male and female mice for Msh4 and Msh5 are reportedly infertile due to meiotic arrest. In humans, MSH4 is associated with male and female gonadal failure, with distinct variations in the MutS domain V.STUDY DESIGN, SIZE, DURATIONThis was a retrospective genetics study of a consanguineous family with multiple cases of gonadal failure in both genders. The subject family was recruited in Iran, in 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSThe proband who is affected by POI, an NOA brother, a fertile sister and their parents were subjected to WES. The discovered variant was validated in these individuals, and the rest of the family was also genotyped by Sanger sequencing. The variant was not detected in 800 healthy Iranian individuals from the Iranome database nor in 30 sporadic NOA and 30 sporadic POI patients. Suggested effect in aberrant splicing was studied by RT-PCR. Moreover, protein homology modeling was used to further investigate the amino acid substitution in silico.MAIN RESULTS AND THE ROLE OF CHANCEThe discovered variant is very rare and has never been reported in the homozygous state. It occurs in the ATPase domain at Serine 754, the first residue within the highly conserved MutS signature motif, substituting it with a Leucine. All variant effect prediction tools indicated this variant as deleterious. Since the substitution occurs immediately before the Walker B motif at position 755, further investigations based on protein homology were conducted. Considering the modeling results, the nature of the substituted amino acid residue and the distances between p. S754L variation and the residues of the Walker B motif suggested the possibility of conformational changes affecting the ATPase activity of the protein.LARGE SCALE DATAWe have submitted dbSNP entry rs377712900 to ClinVar under SCV001169709, SCV001169708 and SCV001142647 for oligozoospermia, NOA and POI, respectively.LIMITATIONS, REASONS FOR CAUTIONStudies in model organisms can shed more light on the role of this variant as our results were obtained by variant effect prediction tools and protein homology modeling.WIDER IMPLICATIONS OF THE FINDINGSIdentification of variants in meiotic genes should improve genetic counseling for both male and female infertility. Also, as two of our NOA patients underwent testicular sperm extraction (TESE) with no success, ruling out the existence of pathogenic variants in meiotic genes in such patients prior to TESE could prove useful.STUDY FUNDING/COMPETING INTEREST(S)This study was financially supported by Royan Institute in Tehran, Iran, and Institut Pasteur in Paris, France. The authors declare no competing interests.TRIAL REGISTRATION NUMBERN/A

Published
2021

24. Treating leishmaniasis in Amazonia, part 2: Multi-target evaluation of widely used plants to understand medicinal practices

Author

Emeline Houël, Marine Ginouves, Nadine Azas, Eliane Bourreau, Véronique Eparvier, Sébastien Hutter, Adeline Knittel-Obrecht, Arnaud Jahn-Oyac, Ghislaine Prévot, Pascal Villa, Catherine Vonthron-Sénécheau, Guillaume Odonne, Ecologie des forêts de Guyane (UMR ECOFOG), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-AgroParisTech-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Guyane (UG), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Plate-forme de chimie biologique intégrative de Strasbourg (PCBiS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Ecologie, Evolution, Interactions des Systèmes amazoniens (LEEISA), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS), This work was supported by an 'Investissement d’Avenir' grant managed by the Agence Nationale de la Recherche (CEBA: ANR-10-LABX-25-01)., and ANR-10-LABX-0025,CEBA,CEnter of the study of Biodiversity in Amazonia(2010)

Subjects
History, MESH: Leishmaniasis, Plantago major L, Polymers and Plastics, MESH: THP-1 Cells, THP-1 Cells, MESH: Leishmania, Antiprotozoal Agents, MESH: Plant Extracts, MESH: Hep G2 Cells, MESH: Plants, Medicinal, Industrial and Manufacturing Engineering, [SHS]Humanities and Social Sciences, Immunomodulation, Mice, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Discovery, Animals, HaCaT Cells, Humans, MESH: RAW 264.7 Cells, MESH: Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Business and International Management, MESH: Antiprotozoal Agents, Leishmaniasis, MESH: Mice, Pharmacology, Leishmania, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Plants, Medicinal, MESH: Humans, Plant Extracts, Hep G2 Cells, Plant use pattern, MESH: Leukocytes, Mononuclear, RAW 264.7 Cells, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infected macrophages, MESH: HaCaT Cells, MESH: Medicine, Traditional, Leukocytes, Mononuclear, Bixa orellana L, [SDV.IMM]Life Sciences [q-bio]/Immunology, Medicine, Traditional, MESH: Brazil, Brazil
Abstract

International audience; Ethnopharmacological relevanceLeishmaniasis are widely distributed among tropical and subtropical countries, and remains a crucial health issue in Amazonia. Indigenous groups across Amazonia have developed abundant knowledge about medicinal plants related to this pathology.Aim of the studyWe intent to explore the weight of different pharmacological activities driving taxa selection for medicinal use in Amazonian communities. Our hypothesis is that specific activity against Leishmania parasites is only one factor along other (anti-inflammatory, wound healing, immunomodulating, antimicrobial) activities.Materials and methodsThe twelve most widespread plant species used against leishmaniasis in Amazonia, according to their cultural and biogeographical importance determined through a wide bibliographical survey (475 use reports), were selected for this study. Plant extracts were prepared to mimic their traditional preparations. Antiparasitic activity was evaluated against promastigotes of reference and clinical New-World strains of Leishmania (L. guyanensis, L. braziliensis and L. amazonensis) and L. amazonensis intracellular amastigotes. We concurrently assessed the extracts immunomodulatory properties on PHA-stimulated human PBMCs and RAW264.7 cells, and on L. guyanensis antigens-stimulated PBMCs obtained from Leishmania-infected patients, as well as antifungal activity and wound healing properties (human keratinocyte migration assay) of the selected extracts. The cytotoxicity of the extracts against various cell lines (HFF1, THP-1, HepG2, PBMCs, RAW264.7 and HaCaT cells) was also considered. The biological activity pattern of the extracts was represented through PCA analysis, and a correlation matrix was calculated.ResultsSpondias mombin L. bark and Anacardium occidentale L. stem and leaves extracts displayed high anti-promatigotes activity, with IC50 ≤ 32 μg/mL against L. guyanensis promastigotes for S. mombin and IC50 of 67 and 47 μg/mL against L. braziliensis and L. guyanensis promastigotes, respectively, for A. occidentale. In addition to the antiparasitic effect, antifungal activity measured against C. albicans and T. rubrum (MIC in the 16–64 μg/mL range) was observed. However, in the case of Leishmania amastigotes, the most active species were Bixa orellana L. (seeds), Chelonantus alatus (Aubl.) Pulle (leaves), Jacaranda copaia (Aubl.) D. Don. (leaves) and Plantago major L. (leaves) with IC50 < 20 μg/mL and infection rates of 14–25% compared to the control. Concerning immunomodulatory activity, P. major and B. orellana were highlighted as the most potent species for the wider range of cytokines in all tested conditions despite overall contrasting results depending on the model. Most of the species led to moderate to low cytotoxic extracts except for C. alatus, which exhibited strong cytotoxic activity in almost all models. None of the tested extracts displayed wound healing properties.ConclusionsWe highlighted pharmacologically active extracts either on the parasite or on associated pathophysiological aspects, thus supporting the hypothesis that antiparasitic activities are not the only biological factor useful for antileishmanial evaluation. This result should however be supplemented by in vivo studies, and attracts once again the attention on the importance of the choice of biological models for an ethnophamacologically consistent study. Moreover, plant cultural importance, ecological status and availability were discussed in relation with biological results, thus contributing to link ethnobotany, medical anthropology and biology.

Published
2022

25. The gut environment regulates bacterial gene expression which modulates susceptibility to bacteriophage infection

Author

Marta Lourenço, Lorenzo Chaffringeon, Quentin Lamy-Besnier, Marie Titécat, Thierry Pédron, Odile Sismeiro, Rachel Legendre, Hugo Varet, Jean-Yves Coppée, Marion Bérard, Luisa De Sordi, Laurent Debarbieux, Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège Doctoral, Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Animalerie Centrale (plateforme) - Central Animal Facility (platform) (C2RA), M.L. is funded as part of the Pasteur-Paris University (PPU) International PhD Program. M.L. is funded by Institut Carnot Pasteur Maladies Infectieuses (ANR 11-CARN 017-01). L.D.S. is funded by a Roux-Cantarini Fellowship from the Institut Pasteur (Paris, France). L.C. is funded by a PhD Fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche, France, École Doctorale 394. Q.L.-B. is funded by École Doctorale FIRE - Programme Bettencourt. M.T. received a fellowship from Fondation DigestScience (Lille, France). The transcriptome and epigenome Platform is part of the France Génomique consortium (ANR10-NBS-09-08)., We thank Jorge Moura de Sousa for writing the customized R script for the pairwise comparisons between lists of genes from the different samples and for critically reading the manuscript. We thank Dwayne Roach and Anne Chevallereau for valuable discussions. We thank the Genetics of Biofilms team (Jean-Marc Ghigo) of Institut Pasteur and in particular Anne-Aurélie Lopes for training on the biofilm assays and Christophe Beloin for access to the ASKA plasmids collection. We thank the members of the Centre for Gnotobiology Platform of the Institut Pasteur (Thierry Angélique, Eddie Maranghi, Martine Jacob, Jérome Toutain, and Marisa Gabriela Lopez Dieguez) for their help with the animal work., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Varet, Hugo, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID

Subjects
intestinal microbiota, MESH: Gene Expression, [SDV]Life Sciences [q-bio], Gene Expression, enteric pathogens, Microbiology, auto-inducer, flagellum, Mice, transcriptomics, Virology, Escherichia coli, Animals, Bacteriophages, MESH: Animals, MESH: Bacteriophages, MESH: Mice, Bacteria, MESH: Escherichia coli, lipopolysaccharide, [SDV] Life Sciences [q-bio], MESH: Bacteria, motility, Genes, Bacterial, Parasitology, biofilms, MESH: Genes, Bacterial, gene regulation
Abstract

International audience; Abundance and diversity of bacteria and their viral predators, bacteriophages (phages), in the digestive tract are associated with human health. Particularly intriguing is the long-term coexistence of these two antagonistic populations. We performed genome-wide RNA sequencing on a human enteroaggregative Escherichia coli isolate to identify genes differentially expressed between in vitro conditions and in murine intestines. We experimentally demonstrated that four of these differentially expressed genes modified the interactions between E. coli and three virulent phages by either increasing or decreasing its susceptibility/resistance pattern and also by interfering with biofilm formation. Therefore, the regulation of bacterial genes expression during the colonization of the digestive tract influences the coexistence of phages and bacteria, highlighting the intricacy of tripartite relationships between phages, bacteria, and the animal host in intestinal homeostasis.

Published
2022

26. Mechanistic insights into consumption of the food additive xanthan gum by the human gut microbiota

Author

Matthew P. Ostrowski, Sabina Leanti La Rosa, Benoit J. Kunath, Andrew Robertson, Gabriel Pereira, Live H. Hagen, Neha J. Varghese, Ling Qiu, Tianming Yao, Gabrielle Flint, James Li, Sean P. McDonald, Duna Buttner, Nicholas A. Pudlo, Matthew K. Schnizlein, Vincent B. Young, Harry Brumer, Thomas M. Schmidt, Nicolas Terrapon, Vincent Lombard, Bernard Henrissat, Bruce Hamaker, Emiley A. Eloe-Fadrosh, Ashootosh Tripathi, Phillip B. Pope, Eric C. Martens, Norwegian University of Life Sciences (NMBU), Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], US Department of Energy Joint Genome Institute, Walnut Creek CA, USA, DOE Joint Genome Institute [Walnut Creek], Department of Microbiology and Immunology, University of Michigan Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of British Columbia (UBC), Paul Scherrer Institute (PSI), Architecture et fonction des macromolécules biologiques (AFMB), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Dietary Fiber, Microbiology (medical), MESH: Humans, [SDV]Life Sciences [q-bio], Polysaccharides, Bacterial, Immunology, MESH: Food Additives, Cell Biology, Applied Microbiology and Biotechnology, Microbiology, MESH: Gastrointestinal Microbiome, Gastrointestinal Microbiome, Mice, MESH: Dietary Fiber, Genetics, Animals, Humans, Food Additives, MESH: Animals, MESH: Polysaccharides, Bacterial, MESH: Mice
Abstract

International audience; Processed foods often include food additives such as xanthan gum, a complex polysaccharide with unique rheological properties, that has established widespread use as a stabilizer and thickening agent. Xanthan gum's chemical structure is distinct from those of host and dietary polysaccharides that are more commonly expected to transit the gastrointestinal tract, and little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other dietary fibre polysaccharides. Here we show that the ability to digest xanthan gum is common in human gut microbiomes from industrialized countries and appears contingent on a single uncultured bacterium in the family Ruminococcaceae. Our data reveal that this primary degrader cleaves the xanthan gum backbone before processing the released oligosaccharides using additional enzymes. Some individuals harbour Bacteroides intestinalis that is incapable of consuming polymeric xanthan gum but grows on oligosaccharide products generated by the Ruminococcaceae. Feeding xanthan gum to germfree mice colonized with a human microbiota containing the uncultured Ruminococcaceae supports the idea that the additive xanthan gum can drive expansion of the primary degrader Ruminococcaceae, along with exogenously introduced B. intestinalis. Our work demonstrates the existence of a potential xanthan gum food chain involving at least two members of different phyla of gut bacteria and provides an initial framework for understanding how widespread consumption of a recently introduced food additive influences human microbiomes.

Published
2022

27. Functional compensation precedes recovery of tissue mass following acute liver injury

Author

Ira Fleming, Carolyn Winston, Benjamin Kruft, Alex K. Shalek, Wolfram Goessling, Satdarshan P.S. Monga, Florian Mueller, Sungjin Ko, Udayan Apte, Chad Walesky, Kellie E. Kolb, Jake Henderson, Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), Institute of Medical Engineering & Science [Cambridge, MA] (IMES), Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Ragon Institute of MGH, MIT and Harvard, Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Department of Pharmacology, Toxicology, and Therapeutics [Kansas City, KS, USA], University of Kansas Medical Center [Kansas City, KS, USA], Harvard-MIT Division of Health Sciences and Technology [Cambridge], Dana-Farber Cancer Institute [Boston], Harvard Stem Cell Institute [Cambridge, USA] (HSCI), Harvard University, Massachusetts General Hospital [Boston, MA, USA], and C..W. is supported by F32DK111151, the Cholangiocarcinoma Foundation Research Fellowship, and the American Liver Foundation Charles Trey, MD Memorial Post-doctoral Research Fellowship. W.G. is supported by R01DK090311, R01DK105198, R24OD017870, and the Claudia Adams Barr Program for Excellence in Cancer Research. W.G. is a Pew Scholar in Biomedical Sciences. A.K.S. was supported, in part, by the Searle Scholars Program, the Beckman Young Investigator Program, a Sloan Fellowship in Chemistry, the NIH (1DP2GM1194192 & RM1HG0061931), and the MIT Stem Cell Initiative through Fondation MIT. U.A. is supported by R01DK098414. S.P.M is supported by NIH/NIDDK P30DK120531, Pittsburgh Liver Research Centre Grant, and NIH/NIDDK (DK62277, DK100287, and CA204586)

Subjects
0301 basic medicine, MESH: beta Catenin, General Physics and Astronomy, MESH: Cell Cycle, MESH: Mice, Knockout, Biochemistry, Transcriptome, MESH: Hepatocytes, Mice, 0302 clinical medicine, Protein biosynthesis, MESH: Animals, lcsh:Science, Wnt Signaling Pathway, beta Catenin, Mice, Knockout, Multidisciplinary, Fluorescence in situ hybridization, Cell Cycle, MESH: Wnt Signaling Pathway, Wnt signaling pathway, Cell cycle, MESH: Hepatectomy, Liver regeneration, Cell biology, MESH: Wnt Proteins, Liver, 030211 gastroenterology & hepatology, MESH: Liver Regeneration, Reprogramming, Biotechnology, Science, MESH: Acetaminophen, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, Detoxification, Genetics, Animals, Hepatectomy, Transcriptomics, MESH: Mice, Molecular Biology, Acetaminophen, Cell Proliferation, Mechanism (biology), Gene Expression Profiling, Macrophages, MESH: Macrophages, General Chemistry, Regenerative process, Liver Regeneration, Gene expression profiling, Mice, Inbred C57BL, Wnt Proteins, Disease Models, Animal, 030104 developmental biology, Hepatocytes, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Liver function, MESH: Disease Models, Animal, MESH: Liver
Abstract

The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/β-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation., The liver possesses the ability to regenerate following sudden injury. Here, the authors use single-cell RNA-sequencing and in situ transcriptional analyses to identify a new phase of liver regeneration in mice aimed at maintaining essential functions throughout the regenerative process.

Published
2020

28. NSs amyloid formation is associated with the virulence of Rift Valley fever virus in mice

Author

Susann Kummer, Hans-Georg Kräusslich, Psylvia Léger, Steeve Boulant, Jana Koch, Pierre-Yves Lozach, Megan L. Stanifer, Qilin Xin, Michèle Bouloy, Robin Burk, Carmen Nussbaum-Krammer, Carole Tamietti, Marie Flamand, Karsten Richter, Eliana Nachman, Xavier Montagutelli, Heidelberg University Hospital [Heidelberg], Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH), Universität Heidelberg [Heidelberg] = Heidelberg University, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Moléculaire des Bunyavirus, Institut Pasteur [Paris] (IP), Génétique de la souris - Mouse Genetics, This work was supported by grants from CellNetworks Research Group funds, Heidelberg, and from the Deutsche Forschungsgemeinschaft (DFG, LO-2338/1-1 and LO-2338/3-1). It was also supported by a Chinese Scholarship Council fellowship to Q.X, Universität Heidelberg [Heidelberg], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and Institut Pasteur [Paris]

Subjects
0301 basic medicine, Rift Valley Fever, General Physics and Astronomy, Protein aggregation, Viral Nonstructural Proteins, MESH: Virulence, Virulence factor, chemistry.chemical_compound, Mice, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: Rift Valley Fever, MESH: Microscopy, Confocal, MESH: Animals, lcsh:Science, Multidisciplinary, Microscopy, Confocal, MESH: Protein Aggregation, Pathological, Virulence, Virus structures, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Microscopy, Electron, Transmission, MESH: Rift Valley fever virus, Thioflavin, Encephalitis, MESH: Cell Nucleus, Amyloid, MESH: Cell Line, Tumor, Virulence Factors, Prions, Science, MESH: Vero Cells, Amyloidogenic Proteins, macromolecular substances, Biology, Fibril, Protein Aggregation, Pathological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Microscopy, Electron, Transmission, Cell Line, Tumor, mental disorders, medicine, Animals, Humans, Vero Cells, MESH: Mice, MESH: Virulence Factors, Cell Nucleus, MESH: Amyloid, MESH: Amyloidogenic Proteins, MESH: Humans, 030102 biochemistry & molecular biology, General Chemistry, medicine.disease, Rift Valley fever virus, Virology, 030104 developmental biology, chemistry, MESH: HeLa Cells, Vero cell, MESH: Viral Nonstructural Proteins, lcsh:Q, HeLa Cells
Abstract

Amyloid fibrils result from the aggregation of host cell-encoded proteins, many giving rise to specific human illnesses such as Alzheimer’s disease. Here we show that the major virulence factor of Rift Valley fever virus, the protein NSs, forms filamentous structures in the brain of mice and affects mortality. NSs assembles into nuclear and cytosolic disulfide bond-dependent fibrillary aggregates in infected cells. NSs structural arrangements exhibit characteristics typical for amyloids, such as an ultrastructure of 12 nm-width fibrils, a strong detergent resistance, and interactions with the amyloid-binding dye Thioflavin-S. The assembly dynamics of viral amyloid-like fibrils can be visualized in real-time. They form spontaneously and grow in an amyloid fashion within 5 hours. Together, our results demonstrate that viruses can encode amyloid-like fibril-forming proteins and have strong implications for future research on amyloid aggregation and toxicity in general., Rift Valley fever virus (RVFV) can cause severe diseases in humans, including encephalitis. Here the authors show that NSs, the major virulence factor of RVFV, is an amyloidogenic protein forming fibrils in infected mouse brains and causing increased mortality in mice.

Published
2020

29. The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors

Author

Bianca Balbino, Julien Stackowicz, Kari C. Nadeau, Pauline Herviou, Ophélie Godon, Sébastien Brûlé, Delphine Sterlin, Andrew J. Murphy, Vera Voronina, Bruno Iannascoli, Odile Richard-Le Goff, Gaël A. Millot, Macdonald Lynn, Laurent L. Reber, Harris Faith, Pierre Bruhns, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biophysique Moléculaire (Plate-forme), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Regeneron Pharmaceuticals [Tarrytown], Stanford University, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Commission (Marie Skłodowska-Curie Individual Fellowship H2020-MSCA-IF-2014 656086)European 235Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616050)Institut Pasteur initiative for valorizing the applications of research (ValoExpress 2017)INSERM, ATIP-Avenir program'Investissement d’Avenir'(grant ANR-11-INBS-0006)Pasteur -Paris University (PPU) International Ph.DprogramFrench 'Fondation pour la Recherche Médicale FRMAP-HP, ANR-11-INBS-0006,FLI,France Life Imaging(2011), European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Allergy, MESH: Asthma / immunology, Omalizumab, MESH: Anaphylaxis / immunology, Immunoglobulin E, MESH: Mice, Knockout, Mice, MESH: Asthma / pathology, 0302 clinical medicine, Medicine, MESH: Animals, MESH: Drug Eruptions / pathology, Mice, Knockout, biology, Concise Communication, General Medicine, MESH: Drug Eruptions / genetics, 3. Good health, MESH: Anaphylaxis / pathology, MESH: Omalizumab / genetics, 030220 oncology & carcinogenesis, MESH: Drug Eruptions / immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Eruptions, Antibody, medicine.symptom, Anaphylaxis, medicine.drug, MESH: Mutation, MESH: Anaphylaxis / chemically induced, medicine.drug_class, Immunology, Immunoglobulins, Inflammation, Monoclonal antibody, MESH: Receptors, IgG / immunology, 03 medical and health sciences, Immune system, MESH: Omalizumab / adverse effects, Animals, MESH: Receptors, IgG / genetics, MESH: Mice, MESH: Omalizumab / pharmacology, business.industry, Receptors, IgG, MESH: Asthma / drug therapy, medicine.disease, Asthma, 030104 developmental biology, Mutation, Mast cells, MESH: Anaphylaxis / genetics, biology.protein, business
Abstract

International audience; Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of Omalizumab is associated with reported side effects, ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which Omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between Omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of Omalizumab, and demonstrated that this mAb is equally potent as Omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that Omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.

Published
2020

30. Excretion of Cell-Free and Cell-Associated Zika Virus into Breast Milk of Infected Dams and Identification of Antiviral Factors

Author

Sophie Desgraupes, Patricia Jeannin, Antoine Gessain, Pierre-Emmanuel Ceccaldi, Aurore Vidy, Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), S.D. was the recipient of a PhD fellowship from the French ministry of education and research for this project, and We thank Mathieu Hubert (Institut Pasteur) for his participation in the milk collection during the last experiment, Philippe Afonso (Institut Pasteur) for improving the manuscript, Emeline Perthame (Bioinformatics and Biostatistics HUB, Institut Pasteur) for improving the statistical analysis and Valérie Choumet (Institut Pasteur) for helpful advice.

Subjects
MESH: Antiviral Agents, breastfeeding, mother-to-child transmission, milk cells, antiviral, fatty acids, MESH: Zika Virus, Antiviral Agents, Biological Factors, Mice, MESH: Zika Virus Infection, MESH: Pregnancy, Pregnancy, Virology, Animals, Humans, MESH: Animals, MESH: Mice, MESH: Humans, MESH: Milk, Human, Milk, Human, Zika Virus Infection, Zika Virus, MESH: Satellite Viruses, Infectious Disease Transmission, Vertical, MESH: Infectious Disease Transmission, Vertical, Infectious Diseases, Satellite Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Biological Factors, Female, MESH: Female
Abstract

International audience; Zika virus (ZIKV) is a mosquito-borne RNA virus belonging to the Flavivirus genus of the Flaviviridae family. During the 60 years following its discovery in 1947, ZIKV caused little concern for public health as the associated infection was reported as mostly asymptomatic or inducing mild symptoms. However, since 2013, severe neurological symptoms have been associated with ZIKV infection, compelling the World Health Organization to declare a Public Health Emergency of International Concern. Among those symptoms, neurological birth defects may affect children born to mothers infected during pregnancy. Additionally, during the past 8 years, ZIKV transmission through breastfeeding has repeatedly been suggested in epidemiological studies and demonstrated on a mouse model by our team. To better understand the biological factors controlling ZIKV transmission through breastfeeding, we investigated the nature of the viral entities excreted in the breast milk of infected dams and evaluated viral transmission to breastfed pups. We show that both cell-free and cell-associated virus is excreted into breast milk and that ZIKV is efficiently transmitted to the breastfed pups. Additionally, we studied murine breast milk cell types, and identified a majority of mammary luminal cells. Finally, we investigated the effect on ZIKV infectivity of several breast milk components that are antiviral against different viruses such as lactoferrin (LF) and lactalbumin (LA), or free fatty acids (FFA). We showed no effect of LF and LA, whereas FFA inactivated the virus. These results bring new insight concerning the mechanisms of ZIKV transmission during breastfeeding and identify biological factors modulating it. These elements should be considered in risk assessment of ZIKV mother-to-child transmission

Published
2022

31. Physiological synaptic activity and recognition memory require astroglial glutamine

Author

Giselle Cheung, Danijela Bataveljic, Josien Visser, Naresh Kumar, Julien Moulard, Glenn Dallérac, Daria Mozheiko, Astrid Rollenhagen, Pascal Ezan, Cédric Mongin, Oana Chever, Alexis-Pierre Bemelmans, Joachim Lübke, Isabelle Leray, Nathalie Rouach, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), Photophysique et Photochimie Supramoléculaires et Macromoléculaires (PPSM), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institute of Neuroscience and Medicine [Jülich] (INM-1), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry, Psychotherapy and Psychosomatics [Aachen], and Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH)

Subjects
Male, MESH: Hippocampus, Intravital Microscopy, MESH: Mice, Transgenic, Glutamine, Science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Glutamic Acid, MESH: Stereotaxic Techniques, General Physics and Astronomy, Mice, Transgenic, MESH: Cognition, MESH: Rhodamines, Hippocampus, Synaptic Transmission, General Biochemistry, Genetics and Molecular Biology, Stereotaxic Techniques, Mice, MESH: Intravital Microscopy, Cognition, MESH: Recognition, Psychology, MESH: Synaptic Transmission, Animals, MESH: Animals, MESH: Mice, Fluorescent Dyes, Neurons, MESH: Glutamine, Multidisciplinary, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Rhodamines, MESH: Molecular Probes, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Recognition, Psychology, MESH: Glutamic Acid, General Chemistry, MESH: Fluorescent Dyes, MESH: Male, MESH: Astrocytes, MESH: Models, Animal, Astrocytes, Molecular Probes, Models, Animal, ddc:500
Abstract

Nature Communications 13, 753 (2022). doi:10.1038/s41467-022-28331-7, Published by Nature Publishing Group UK, [London]

Published
2022

32. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies

Author

Kenigsbuch, Mor, Bost, Pierre, Halevi, Shahar, Chang, Yuzhou, Chen, Shuo, Ma, Qin, Hajbi, Renana, Schwikowski, Benno, Bodenmiller, Bernd, Fu, Hongjun, Schwartz, Michal, Amit, Ido, University of Zurich, Schwartz, Michal, Amit, Ido, Weizmann Institute of Science [Rehovot, Israël], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), Ohio State University [Columbus] (OSU), The research of I.A. is supported by the Seed Networks for the Human Cell Atlas of the Chan Zuckerberg Initiative, the Thompson Family Foundation Alzheimer’s Research Fund and the Adelis Foundation. I.A. is an Eden and Steven Romick Professorial Chair, supported by the HHMI International Scholar Award, a European Research Council Consolidator Grant (724471-HemTree2.0), an MRA Established Investigator Award (509044), the DFG (SFB/TRR167), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, the Helen and Martin Kimmel awards for innovative investigation and the SCA award of the Wolfson Foundation and Family Charitable Trust. Research in the M.S. laboratory is supported by Advanced European Research Council grants (741744), Israel Science Foundation (ISF) research grant 991/16, and and ISF-Legacy Heritage Bio-Medical Science Partnership research grant 1354/15. We would like to thank the Adelis and Thompson Foundations for their generous support of our AD research. This work is also supported by awards K01-AG056673 and R56-066782–01 from the National Institute on Aging of the National Institutes of Health, R01-GM131399 (Q.M.) from the National Institute of General Medical Sciences, AARF-17–505009 (H.F.) from the Alzheimer’s Association and W81XWH1910309 (H.F.) from the US Department of Defense.

Subjects
MESH: Mice, Transgenic, Mice, Transgenic, Plaque, Amyloid, 610 Medicine & health, Article, MESH: Neurodegenerative Diseases, MESH: Brain, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, MESH: Amyloid beta-Protein Precursor, Animals, Humans, MESH: Animals, MESH: Mice, MESH: Humans, Amyloid beta-Peptides, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, Brain, 2800 General Neuroscience, MESH: Oligodendroglia, Neurodegenerative Diseases, MESH: Amyloid beta-Peptides, MESH: Plaque, Amyloid, Disease Models, Animal, Oligodendroglia, MESH: Disease Models, Animal, 11493 Department of Quantitative Biomedicine, MESH: Alzheimer Disease
Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disease, perturbing neuronal and non-neuronal cell populations. In this study, using single-cell transcriptomics, we mapped all non-immune, non-neuronal cell populations in wild-type and AD model (5xFAD) mouse brains. We identified an oligodendrocyte state that increased in association with brain pathology, which we termed disease-associated oligodendrocytes (DOLs). In a murine model of amyloidosis, DOLs appear long after plaque accumulation, and amyloid-beta (Aβ) alone was not sufficient to induce the DOL signature in vitro. DOLs could be identified in a mouse model of tauopathy and in other murine neurodegenerative and autoimmune inflammatory conditions, suggesting a common response to severe pathological conditions. Using quantitative spatial analysis of mouse and postmortem human brain tissues, we found that oligodendrocytes expressing a key DOL marker (SERPINA3N/SERPINA3 accordingly) are present in the cortex in areas of brain damage and are enriched near Aβ plaques. In postmortem human brain tissue, the expression level of this marker correlated with cognitive decline. Altogether, this study uncovers a shared signature of oligodendrocytes in central nervous system pathologies., Nature Neuroscience, 25 (7), ISSN:1097-6256, ISSN:1546-1726

Published
2022
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33. Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Author

Diana M. Dincã, Louison Lallemant, Anchel González-Barriga, Noémie Cresto, Sandra O. Braz, Géraldine Sicot, Laure-Elise Pillet, Hélène Polvèche, Paul Magneron, Aline Huguet-Lachon, Hélène Benyamine, Cuauhtli N. Azotla-Vilchis, Luis E. Agonizantes-Juárez, Julie Tahraoui-Bories, Cécile Martinat, Oscar Hernández-Hernández, Didier Auboeuf, Nathalie Rouach, Cyril F. Bourgeois, Geneviève Gourdon, Mário Gomes-Pereira, Gomes-Pereira, Mario, ARN toxiques et interactions neurogliales dans l'atteinte cerebrale de la dystrophie myotonique - - DM_Neuroglia2016 - ANR-16-CE16-0005 - AAPG2016 - VALID, Wiring synaptic circuits with astroglial connexins: mechanisms, dynamics and impact for critical period plasticity - AstroWireSyn - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)2016-10-01 - 2021-09-30 - 683154 - VALID, Training, Research and Raising of Public Awareness in Cell Biology and Pathology of Neuroglia - EU-GliaPhD - H2020-EU.1.3. H2020-EU.1.3.1. - 722053 - INCOMING, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Instituto Nacional de Rehabilitacion (INR), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE16-0005,DM_Neuroglia,ARN toxiques et interactions neurogliales dans l'atteinte cerebrale de la dystrophie myotonique(2016), European Project: 683154,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),AstroWireSyn(2016), European Project: 722053,EU-GliaPhD - H2020-EU.1.3. H2020-EU.1.3.1., and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
MESH: Mice, Transgenic, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Physics and Astronomy, Mice, Transgenic, Tissue Adhesions, General Biochemistry, Genetics and Molecular Biology, MESH: Astrocytes / metabolism, Mice, Neurobiology, Transgenic mouse, Trinucleotide repeat, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Myotonic Dystrophy, Myotonic Dystrophy type 1, MESH: Animals, MESH: Mice, Multidisciplinary, MESH: Humans, MESH: Myotonic Dystrophy / metabolism, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, RNA-Binding Proteins, MESH: RNA-Binding Proteins / metabolism, General Chemistry, Neuron, nervous system, Astrocytes, Toxic RNA, RNA, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Tissue Adhesions, Astrocyte, MESH: RNA / genetics
Abstract

Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Here, using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types (neurons, astroglia, and oligodendroglia), we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading, and migration. RNA-dependent toxicity and phenotypes are also found in human transfected glial cells. In line with the cell phenotypes, molecular analyses reveal extensive expression and accumulation of toxic RNA in astrocytes, which result in RNA spliceopathy that is more severe than in neurons. Astrocyte missplicing affects primarily transcripts that regulate cell adhesion, cytoskeleton, and morphogenesis, and it is confirmed in human brain tissue. Our findings demonstrate that DM1 impacts astrocyte cell biology, possibly compromising their support and regulation of synaptic function.

Published
2022

34. H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

Author

Tiphaine M. N. Camarasa, Catherine Fitting, Melanie Hamon, Jean-Marc Cavaillon, Orhan Rasid, Christine Chevalier, Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris], Cytokines et Inflammation, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Work in the M.A.H. laboratory received financial support from Institut Pasteur and the French National Research Agency (ANR-EPIBACTIN). O.R. was supported by a stipend from the Pasteur – Paris University International PhD Program for part of this work. T.M.-N.C. is supported by a fellowship from the Foundation for Medical Research (Mariane Josso Prize)., We would like to thank Olivier Dussurget and Emmanuel Lemichez for the kind gift of the luminescent E. coli, Thomas Kohler and Sven Hammerschmidt for the S. pneumoniae strain, and Ignacio Santecchia for technical assistance with E. coli culture., ANR-17-CE12-0007,EpiBactIn,Modifications epigenomiques induites par l'interaction hote-bacteries(2017), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, MESH: Inflammation, Male, Adoptive cell transfer, Histone methyltransferase activity, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Stimulation, NK cells, Systemic inflammation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, sepsis, Histones, Mice, 0302 clinical medicine, MESH: Animals, lcsh:QH301-705.5, Escherichia coli Infections, MESH: Histones, biology, MESH: Escherichia coli, NK cell memory, Cell biology, Killer Cells, Natural, Histone, Enhancer Elements, Genetic, MESH: Immunologic Memory, MESH: Immunity, Innate, medicine.symptom, epigenetic, MESH: Killer Cells, Natural, MESH: Interferon-gamma, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, medicine, Escherichia coli, Animals, Epigenetics, MESH: Mice, MESH: Escherichia coli Infections, Inflammation, Innate immune system, H3K4me1, Immunotherapy, MESH: Male, Endotoxemia, Immunity, Innate, 030104 developmental biology, lcsh:Biology (General), MESH: Endotoxemia, biology.protein, MESH: Enhancer Elements, Genetic, Immunologic Memory, 030217 neurology & neurosurgery
Abstract

Summary: Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory-like properties, showing increased production of IFNγ upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylation-dependent manner, ensuring a heightened response to secondary stimulation. : Rasid et al. show that sepsis-like systemic inflammation induces a type of long-lasting innate immune memory in NK cells, which can protect from E. coli infection. This is achieved by revealing an enhancer of IFNγ through histone monomethylation. Keywords: NK cells, NK cell memory, sepsis, epigenetic, H3K4me1

Published
2019

35. Targeting Tn-Antigen-Positive Human Tumors with a Recombinant Human Macrophage Galactose C-Type Lectin

Author

François Bulteau, Michel Thépaut, Maxime Henry, Amandine Hurbin, Laetitia Vanwonterghem, Corinne Vivès, Aline Le Roy, Christine Ebel, Olivier Renaudet, Franck Fieschi, Jean-Luc Coll, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Département de Chimie Moléculaire (DCM), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)

Subjects
MESH: HT29 Cells, Pharmaceutical Science, MESH: Spheroids, Cellular, Mice, Nude, MESH: Flow Cytometry, MESH: Recombinant Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, Spheroids, Cellular, Drug Discovery, Tn antigen, MESH: Mice, Nude, cancer, MESH: Microscopy, Confocal, Animals, Humans, MESH: Animals, Antigens, Tumor-Associated, Carbohydrate, Lectins, C-Type, MESH: Mice, 030304 developmental biology, 0303 health sciences, MESH: Humans, Microscopy, Confocal, MESH: Antigens, Tumor-Associated, Carbohydrate, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Surface Plasmon Resonance, Flow Cytometry, Recombinant Proteins, 3. Good health, MESH: Surface Plasmon Resonance, C-type lectin, A549 Cells, 030220 oncology & carcinogenesis, Molecular Medicine, Female, MESH: A549 Cells, MESH: Female, HT29 Cells, MESH: Neoplasm Transplantation, MESH: Lectins, C-Type, Neoplasm Transplantation
Abstract

International audience; Alterations in glycosylation cause the emergence of tumor-associated carbohydrate antigens (TACAs) during tumorigenesis. Truncation of O-glycans reveals the Thomsen nouveau (Tn) antigen, an N-acetylgalactosamine (GalNAc) frequently attached to serine or threonine amino acids, that is accessible on the surface of cancer cells but not on healthy cells. Interestingly, GalNac can be recognized by macrophage galactose lectin (MGL), a type C lectin receptor expressed in immune cells. In this study, recombinant MGL fragments were tested in vitro for their cancer cell-targeting efficiency by flow cytometry and confocal microscopy and in vivo after administration of fluorescent MGL to tumor-bearing mice. Our results demonstrate the ability of MGL to target Tn-positive human tumors without inducing toxicity. This outcome makes MGL, a fragment of a normal human protein, the first vector candidate for in vivo diagnosis and imaging of human tumors and, possibly, for therapeutic applications.

Published
2021

36. Identification of adipocytes as target cells for Leishmania infantum parasites

Author

Schwing, Aurélie, Pisani, Didier, Pomares, Christelle, Majoor, Alissa, Lacas-Gervais, Sandra, Jager, Jennifer, Lemichez, Emmanuel, Marty, Pierre, Boyer, Laurent, Michel, Grégory, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Aix Marseille Université (AMU), Laboratoire de PhysioMédecine Moléculaire (LP2M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CCMA - Centre Commun de Microscopie Appliquée, Université Côte d'Azur (UCA), Toxines bactériennes - Bacterial Toxins, Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), We acknowledge financial support by the Conseil Départemental des Alpes-Maritimes and Conseil Régional PACA. This work was supported by a Grant from the Société Francophone du Diabète (SFD)/Pierre Fabre Médicament 2017., and DELARUE, NADINE

Subjects
Parasitic infection, Science, [SDV]Life Sciences [q-bio], MESH: Disease Susceptibility, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Article, Host-Parasite Interactions, Mice, MESH: Psychodidae, 3T3-L1 Cells, parasitic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Adipocytes, Parasite immune evasion, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, MESH: Animals, Leishmania infantum, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, MESH: 3T3-L1 Cells, MESH: Leishmania infantum, [SDV] Life Sciences [q-bio], Disease Models, Animal, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Adipose Tissue, MESH: Leishmaniasis, Visceral, Medicine, Leishmaniasis, Visceral, Disease Susceptibility, Psychodidae, MESH: Disease Models, Animal, MESH: Adipose Tissue
Abstract

International audience; Leishmania infantum is the causative agent of visceral leishmaniasis transmitted by the bite of female sand flies. According to the WHO, the estimated annual incidence of leishmaniasis is one million new cases, resulting in 30,000 deaths per year. The recommended drugs for treating leishmaniasis include Amphotericin B. But over the course of the years, several cases of relapses have been documented. These relapses cast doubt on the efficiency of actual treatments and raise the question of potential persistence sites. Indeed, Leishmania has the ability to persist in humans for long periods of time and even after successful treatment. Several potential persistence sites have already been identified and named as safe targets. As adipose tissue has been proposed as a sanctuary of persistence for several pathogens, we investigated whether Leishmania infantum could be found in this tissue. We demonstrated both in cell cultures and in vivo that Leishmania infantum was able to infect adipocytes. Altogether our results suggest adipocytes as a ‘safe target’ for Leishmania infantum parasites.

Published
2021

37. Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

Author

Scekic-Zahirovic, Jelena, Sanjuan-Ruiz, Inmaculada, Kan, Vanessa, Megat, Salim, De Rossi, Pierre, Dieterlé, Stéphane, Cassel, Raphaelle, Jamet, Marguerite, Kessler, Pascal, Wiesner, Diana, Tzeplaeff, Laura, Demais, Valérie, Sahadevan, Sonu, Hembach, Katharina M, Muller, Hans-Peter, Picchiarelli, Gina, Mishra, Nibha, Antonucci, Stefano, Dirrig-Grosch, Sylvie, Kassubek, Jan, Rasche, Volker, Ludolph, Albert, Boutillier, Anne-Laurence, Roselli, Francesco, Polymenidou, Magdalini, Lagier-Tourenne, Clotilde, Liebscher, Sabine, Dupuis, Luc, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians University [Munich] (LMU), Universität Zürich [Zürich] = University of Zurich (UZH), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CRBS - Centre de Recherche en Biomédecine de Strasbourg (Inserm UMS38/UNISTRA), University of Ulm (UUlm), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Centre de Neurochimie, Harvard Medical School [Boston] (HMS), Harvard University [Cambridge], Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Université de Strasbourg Inserm Faculté de médecine, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universität München (LMU), University hospital of Zurich [Zurich], Universität Ulm - Ulm University [Ulm, Allemagne], Massachusetts Institute of Technology (MIT), Ludwig-Maximilians University Hospital (LMU Munich), ANR-16-CE92-0031,EpiFUS,Rôle de FUS dans la régulation des modifications épigénétiques : conséquences pour la sclérose latérale amyotrophique et la démence frontotemporale(2016), ANR-16-CE16-0015,ToFU,Interactions entre TAU, FUS et TDP-43 dans les maladies neurodégénératives(2016), ANR-19-CE17-0016,SPREADALS,Propagation et toxicité des facteurs pathogéniques de la sclérose latérale amyotrophique(2019), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Anne Laurence, Boutillier, Rôle de FUS dans la régulation des modifications épigénétiques : conséquences pour la sclérose latérale amyotrophique et la démence frontotemporale - - EpiFUS2016 - ANR-16-CE92-0031 - AAPG2016 - VALID, Interactions entre TAU, FUS et TDP-43 dans les maladies neurodégénératives - - ToFU2016 - ANR-16-CE16-0015 - AAPG2016 - VALID, Propagation et toxicité des facteurs pathogéniques de la sclérose latérale amyotrophique - - SPREADALS2019 - ANR-19-CE17-0016 - AAPG2019 - VALID, University of Zurich, Liebscher, Sabine, Dupuis, Luc, Centre de Recherche en Biomédecine de Strasbourg (CRBS), and Dieterle, Stéphane

Subjects
Male, Cytoplasm, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Gene Expression, Synaptic Transmission, MESH: Synapses, Mice, MESH: Animals, Gene Knock-In Techniques, MESH: Amyotrophic Lateral Sclerosis, MESH: Gene Knock-In Techniques, metabolism [RNA-Binding Protein FUS], Motor Neurons, MESH: RNA-Binding Protein FUS, FUS protein, mouse, 3100 General Physics and Astronomy, [SDV] Life Sciences [q-bio], genetics [Amyotrophic Lateral Sclerosis], Phenotype, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, ddc:500, MESH: Motor Neurons, MESH: Mutation, MESH: Gene Expression, Science, 610 Medicine & health, 1600 General Chemistry, Genetics and Molecular Biology, MESH: Phenotype, Article, 1300 General Biochemistry, Genetics and Molecular Biology, MESH: Mice, Inbred C57BL, MESH: Synaptic Transmission, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, metabolism [Cytoplasm], metabolism [Amyotrophic Lateral Sclerosis], MESH: Cytoplasm, Amyotrophic Lateral Sclerosis, General Chemistry, metabolism [Motor Neurons], metabolism [Synapses], MESH: Male, Mice, Inbred C57BL, physiology [Synaptic Transmission], General Biochemistry, Mutation, Synapses, RNA-Binding Protein FUS, 11493 Department of Quantitative Biomedicine, genetics [RNA-Binding Protein FUS], MESH: Female
Abstract

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization., Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.

Published
2021

38. Season, weight, and age, but not transmissible cancer, affect tick loads in the endangered Tasmanian devil

Author

Sophia Belkhir, Rodrigo Hamede, Frédéric Thomas, Beata Ujvari, Antoine M. Dujon, Deakin University [Burwood], École normale supérieure de Lyon (ENS de Lyon), University of Tasmania [Hobart, Australia] (UTAS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), and ANR-18-CE35-0009,TRANSCAN,ECOLOGIE ET EVOLUTION DES CANCERS TRANSMISSIBLES(2018)

Subjects
Microbiology (medical), Male, MESH: Transgenes, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Dependovirus, Microbiology, Tasmania, Ticks, MESH: Genetic Vectors, MESH: Plasmids, Neoplasms, Genetics, Animals, MESH: Animals, Molecular Biology, MESH: Mice, Ecology, Evolution, Behavior and Systematics, Cancer, MESH: Ticks, MESH: Genetic Therapy, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Body Weight, Age Factors, MESH: Receptors, Antigen, T-Cell, Tick Infestations, Infectious Diseases, Marsupialia, Sarcophilus harrisii, Female, Ectoparasites, MESH: Tick Infestations, Seasons, MESH: Virus Integration
Abstract

International audience; The Tasmanian devil (Sarcophilus harrisii) is a carnivorous marsupial threatened by a transmissible cancer, devil facial tumour disease (DFTD). While we have a good understanding of the effect of the transmissible cancer on its host, little information is available about its potential interactions with ectoparasites. With this study, we aimed to determine the factors driving tick loads in a DFTD affected Tasmanian devil population, using long-term mark-recapture data. We investigated the effect of a range of life history traits (age, weight, sex, body condition) and of DFTD (time since DFTD arrival and presence of tumours) on the ectoparasitic tick load of the devils. Mixed effect models revealed that tick load in Tasmanian devils was primarily driven by season, weight, body condition and age. Young devils had more ticks compared to older or healthier devils. The reduction in Tasmanian devil population size over the past 14 years at the studied site had little effect on tick infestation. We also found that devils infected by DFTD had a similar tick load compared to those free of observable tumours, suggesting no interaction between the transmissible cancer and tick load. Our study highlights seasonality and life cycle as primary drivers of tick infestation in Tasmanian devils and the need for further investigations to integrate devil stress and immune dynamics with ectoparasite counts.

Published
2021

39. Translational development of a tumor junction opening technology

Author

Jiho Kim, Bing-Mae Chen, Audrey Germond, Roffler Steve, Sucheol Gil, Laxman Savergave, Sanjay Singh, Hongjie Wang, Chang Li, Andre Lieber, Pascal Fender, Darrick Carter, Audrey Baldessari, Arjun Raghuwanshi, Charles W. Drescher, Swarnendu Kaviraj, PAI Life Sciences, Inc, Huazhong University of Science and Technology [Wuhan] (HUST), Complexe de recherche interprofessionnel en aérothermochimie (CORIA), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Gennova Biopharmaceuticals, Ltd, Division of Medical Genetics [Seattle], University of Washington [Seattle], Washington National Primate Research Center [Seattle], Institute of Biomedical Sciences [Taipei, Taiwan], Academia Sinica, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Public Health Sciences Division, and Fred Hutchinson Cancer Research Center [Seattle] (FHCRC)

Subjects
Engineering, Technology, MESH: Tight Junctions, Tight Junctions, MESH: Recombinant Proteins, MESH: Doxorubicin, Mice, Antineoplastic Combined Chemotherapy Protocols, Animals, Humans, MESH: Animals, MESH: Mice, Cyclophosphamide, Ovarian Neoplasms, Multidisciplinary, MESH: Technology, MESH: Humans, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, MESH: Cyclophosphamide, Recombinant Proteins, Cell biology, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Ovarian Neoplasms, Doxorubicin, Female, business, MESH: Female
Abstract

Our goal is to overcome treatment resistance in ovarian cancer patients which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2) positive tight junctions between malignant cells that prevents drug penetration into the tumor. We have generated JO4, a recombinant protein that binds to DSG2 resulting in the transient opening of junctions in epithelial tumors. Here we present studies toward the clinical translation of c-JO4 in combination with PEGylated liposomal doxorubicin/Doxil for ovarian cancer therapy. A manufacturing process for cGMP compliant production of JO4 was developed resulting in c-JO4. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous c-JO4 plus Doxil (four cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against c-JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL-6 and TNFα. Pretreatment with steroids and cyclophosphamide reduced anti-c-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.

Published
2021

40. In vivo commensal control of Clostridioides difficile virulence

Author

Mario L. Arrieta-Ortiz, Johann Peltier, Andrew B. Onderdonk, Selva Rupa Christinal Immanuel, Narjol Gonzalez-Escalona, Nicholas DiBenedetto, Richard Lavin, Nitin S. Baliga, Marc W. Allard, Maria Hoffman, Abraham L. Sonenshein, Yan Luo, Christopher K Cummins, Brintha P. Girinathan, Lynn Bry, Bruno Dupuy, Jay N. Worley, Mary L. Delaney, Georg K. Gerber, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), National Center for Biotechnology Information (NCBI), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institute for Systems Biology [Seattle] (ISB), U.S. Food and Drug Administration (FDA), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), Tufts University School of Medicine [Boston], This work was supported by the BWH Precision Medicine Institute, R01AI153605 from the National Institute of Allergy and Infectious Diseases (NIAID) and P30DK034854 from the National Institute of Diabetes, Digestive and Kidney Diseases to L.B., R01AI128215, R01AI141953, and U19AI135976 from NIAID and IIBR-2042948 from the National Science Foundation to N.S.B., B.P.G. was supported by T32 HL007627, and the work of J.N.W. was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. J.P. received support from the Institut Pasteur (Bourse ROUX). This work was conducted by authors from the FDA working as official U.S. Government employees and for which no additional external funding was utilized.

Subjects
MESH: Clostridioides difficile, MESH: Amino Acids, colitis, Systems biology, MESH: Clostridium Infections, [SDV]Life Sciences [q-bio], gnotobiotic mouse, Clostridium sardiniense, Virulence, MESH: Butyrates, Biology, MESH: Virulence, medicine.disease_cause, Microbiology, MESH: Clostridiales, MESH: Fermentation, Clostridia, MESH: Gene Expression Profiling, conventional mouse, In vivo, Virology, MESH: Germ-Free Life, MESH: Severity of Illness Index, medicine, Paraclostridium bifermentans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Colitis, Pathogen, MESH: Mice, MESH: Gene Regulatory Networks, MESH: Gene Expression Regulation, Bacterial, metatranscriptomics, MESH: Symbiosis, Toxin, Host (biology), Clostridioides difficile, MESH: Clostridium, MESH: Arginine, MESH: Cecum, biology.organism_classification, medicine.disease, metabolomics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Systems Biology, Parasitology, carbon source enrichment analysis, anaerobe metabolism
Abstract

International audience; Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense, succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen's metabolism, gene regulatory networks, and toxin production. Oral administration of P. bifermentans rescues conventional, clindamycin-treated mice from lethal C. difficile infection in a manner similar to that of monocolonized animals, thereby supporting the therapeutic potential of this commensal species. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo.

Published
2021

41. Transcriptome Profile During Rabies Virus Infection: Identification of Human CXCL16 as a Potential New Viral Target

Author

Lena Feige, Inés Sáenz-de-Santa-María, Beatrice Regnault, Rachel Lavenir, Anthony Lepelletier, Ala Halacu, Randrianasolo Rajerison, Sylvie Diop, Chhor Nareth, Jean-Marc Reynes, Philippe Buchy, Hervé Bourhy, Laurent Dacheux, Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre National de Référence de la Rage - National Reference Center Rabies (CNR), Centre collaborateur de l'OMS - Rage / World Health Organization Collaboration Centres - Rabies (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Université Paris Cité (UPCité), Trafic membranaire et Pathogénèse - Membrane Traffic and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génopole, Institut Pasteur [Paris] (IP), National Centre for Public Health [Chisinau, Republic of Moldova], Hôpital Joseph Raseta Befelatanana, CHU d’Antananarivo, CHNU Fann Dakar, Calmette Hospital [Phnom Penh], Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur du Cambodge, and LF was supported by the Pasteur - Paris University (PPU) International PhD Program. This work was partially funded by Institut Pasteur International Network Actions Concertees InterPasteuriennes (2003/687). We are also grateful to Santé publique France for the financial support of the National Reference Centre for Rabies.

Subjects
brain, rabies, Microbiology, immune response, neuroinflammation, MESH: Dogs, Mice, MESH: Brain, Cellular and Infection Microbiology, Dogs, MESH: Rabies, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Animals, Humans, MESH: Animals, human, MESH: Mice, mouse, Original Research, MESH: Humans, MESH: Transcriptome, Chemokine CXCL16, QR1-502, CXCL16, MESH: Rabies virus, Disease Models, Animal, Rabies virus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Chemokine CXCL16, MESH: Disease Models, Animal, transcriptome
Abstract

International audience; Rabies virus (RABV), the causative agent for rabies disease is still presenting a major public health concern causing approximately 60,000 deaths annually. This neurotropic virus (genus Lyssavirus , family Rhabdoviridae ) induces an acute and almost always fatal form of encephalomyelitis in humans. Despite the lethal consequences associated with clinical symptoms of rabies, RABV limits neuro-inflammation without causing major histopathological lesions in humans. Nevertheless, information about the mechanisms of infection and cellular response in the central nervous system (CNS) remain scarce. Here, we investigated the expression of inflammatory genes involved in immune response to RABV (dog-adapted strain Tha) in mice, the most common animal model used to study rabies. To better elucidate the pathophysiological mechanisms during natural RABV infection, we compared the inflammatory transcriptome profile observed at the late stage of infection in the mouse brain (cortex and brain stem/cerebellum) with the ortholog gene expression in post-mortem brain biopsies of rabid patients. Our data indicate that the inflammatory response associated with rabies is more pronounced in the murine brain compared to the human brain. In contrast to murine transcription profiles, we identified CXC motif chemokine ligand 16 ( CXCL16 ) as the only significant differentially expressed gene in post-mortem brains of rabid patients. This result was confirmed in vitro , in which Tha suppressed interferon alpha (IFN-α)-induced CXCL16 expression in human CNS cell lines but induced CXCL16 expression in IFN-α-stimulated murine astrocytes. We hypothesize that RABV-induced modulation of the CXCL16 pathway in the brain possibly affects neurotransmission, natural killer (NK) and T cell recruitment and activation. Overall, we show species-specific differences in the inflammatory response of the brain, highlighted the importance of understanding the potential limitations of extrapolating data from animal models to humans.

Published
2021

42. Histamine in murine narcolepsy: What do genetic and immune models tell us?

Author

Anne-Laure Morel, Silvia Melzi, Roland S. Liblau, Céline Scoté-Blachon, Yves Dauvilliers, Christelle Peyron, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Peyron, Christelle, APPEL À PROJETS GÉNÉRIQUE 2018 - Physiopathologie de la narcolepsie de type 1 - - NARCO-T12018 - ANR-18-CE17-0014 - AAPG2018 - VALID, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), and ANR-18-CE17-0014,NARCO-T1,Physiopathologie de la narcolepsie de type 1(2018)

Subjects
MESH: Histamine* / metabolism, [SDV]Life Sciences [q-bio], MESH: Histidine Decarboxylase / genetics, Histidine Decarboxylase, Mixed Function Oxygenases, Mice, chemistry.chemical_compound, MESH: Narcolepsy* / genetics, 0302 clinical medicine, MESH: Orexins / metabolism, MESH: Animals, hypothalamus, 0303 health sciences, Microglia, General Neuroscience, MESH: Mixed Function Oxygenases, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypothalamus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Histamine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, RNA, Messenger, sleep, MESH: Mice, Neuroinflammation, MESH: RNA, Messenger, Narcolepsy, 030304 developmental biology, MESH: Narcolepsy* / metabolism, Orexins, MESH: Humans, Histaminergic, medicine.disease, Pons, Orexin, Endocrinology, orexin, nervous system, chemistry, Neurology (clinical), hypocretin, 030217 neurology & neurosurgery
Abstract

International audience; An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with narcolepsy type 1 (NT1). In quest for enlightenment, we evaluate whether an increase in HDC cell number and expression level would be detected in mouse models of the disease, in order to provide proof of concepts reveling possible mechanisms of compensation for the loss of orexin neurons, and/or of induced expression as a consequence of local neuroinflammation, a state that likely accompanies NT1. To further explore the compensatory hypothesis, we also study the noradrenergic wake-promoting system. Immunohistochemistry for HDC, orexin, and melanin-concentrating hormone (MCH) was used to count neurons. Quantitative-PCR of HDC, orexin, MCH, and tyrosine-hydroxylase was performed to evaluate levels of mRNA expression in the hypothalamus or the dorsal pons. Both quantifications were achieved in genetic and neuroinflammatory models of narcolepsy with major orexin impairment, namely the orexin-deficient (Orex-KO) and orexin-hemagglutinin (Orex-HA) mice respectively. The number of HDC neurons and mRNA expression level were unchanged in Orex-KO mice compared to controls. Similarly, we found no change in tyrosine-hydroxylase mRNA expression in the dorsal pons between groups. Further, despite the presence of protracted local neuroinflammation as witnessed by the presence of reactive microglia, we found no change in the number of neurons nor the expression of HDC in Orex-HA mice compared to controls. Importantly, no correlation was found in all conditions between HDC and orexin. Our findings indicate that, in mice, the expression of histamine and noradrenalin, two wake-promoting systems, are not modulated by orexin level whether the lack of orexin is constitutive or induced at adult age, showing thus no compensation. They also show no recruitment of histamine by local neuroinflammation. Further studies will be needed to further define the role of histamine in the pathophysiology of NT1.

Published
2021

43. Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

Author

Michèle Carlier, Lucie Brosse, Pierre L. Roubertoux, Laurent Fasano, Mehdi Metwaly, Paolo Gubellini, Yasmine Belaidouni, Ahmed Fatmi, Pascal Salin, Dorian Chabbert, Jordan Molitor, Xavier Caubit, Lydia Kerkerian-Le Goff, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de psychologie cognitive (LPC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), Gubellini, Paolo, Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique - - TSHZ3inASD2017 - ANR-17-CE16-0030 - AAPG2017 - VALID, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix-Marseille Univ, CNRS, IBDM, UMR7288, Marseille, France, and ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017)

Subjects
striatal cholinergic interneurons, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], MESH: Autistic Disorder, Striatum, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Haploinsufficiency, Biology, MESH: Synapses, Cellular and Molecular Neuroscience, 03 medical and health sciences, Mice, 0302 clinical medicine, stereotyped behaviors, Interneurons, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Conditional gene knockout, medicine, Animals, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, MESH: Mice, Biological Psychiatry, 030304 developmental biology, MESH: Autism Spectrum Disorder, 0303 health sciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, MESH: Interneurons, Autism spectrum disorder (ASD), cortical projection neurons, Psychiatry and Mental health, Electrophysiology, TSHZ3, sociability, medicine.anatomical_structure, nervous system, Autism spectrum disorder, Cerebral cortex, Synapses, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cholinergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Haploinsufficiency, Neuroscience, 030217 neurology & neurosurgery
Abstract

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. We show that in the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABA interneurons, while not in cholinergic interneurons or glial cells. TSHZ3-expressing cells, which are predominantly SCINs in the striatum, represent a low proportion of neurons in the ascending cholinergic projection system. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and plasticity at corticostriatal synapses, with neither cortical neuron loss nor impaired layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

Published
2021

44. Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice

Author

Margaux Wieckowski, Stéphanie Ranga, Delphine Moison, Sébastien Messiaen, Sonia Abdallah, Sylvie Granon, René Habert, Virginie Rouiller-Fabre, Gabriel Livera, Marie-Justine Guerquin, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut des Neurosciences Paris-Saclay (NeuroPSI), and Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, endocrine system, germ cells, γ-ray, QH301-705.5, MESH: Leydig Cells, Article, MESH: Prenatal Exposure Delayed Effects, reproduction, Mice, MESH: Phenols, MESH: Pregnancy, Bisphenol A, Phenols, Pregnancy, MESH: Benzhydryl Compounds, Animals, Humans, MESH: Animals, Biology (General), Benzhydryl Compounds, QD1-999, MESH: Mice, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Leydig Cells, MESH: Gamma Rays, MESH: Male, Chemistry, Radiation Injuries, Experimental, endocrine disruptors, Gamma Rays, MESH: Radiation Injuries, Experimental, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Prenatal Exposure Delayed Effects, MESH: HeLa Cells, Female, MESH: Female, HeLa Cells
Abstract

International audience; For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions.

Published
2021

45. Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe

Author

Philippe J Sansonetti, Giulia Nigro, Antonin Levy, Aline Stedman, Nigro, Giulia, Protection du stress des cellules souches intestinales : la cellule, la niche et le microbiote - - i-Stress2017 - ANR-17-CE14-0022 - AAPG2017 - VALID, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), Collège de France (CdF (institution)), Microenvironnement et Immunité - Microenvironment and Immunity, and ANR-17-CE14-0022,i-Stress,Protection du stress des cellules souches intestinales : la cellule, la niche et le microbiote(2017)

Subjects
MESH: Oxidation-Reduction, General Chemical Engineering, [SDV]Life Sciences [q-bio], Flow cytometry analysis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Organoids, medicine.disease_cause, Murine intestinal organoids, General Biochemistry, Genetics and Molecular Biology, Flow cytometry, Mice, Live cell imaging, Live imaging detection, ROS-sensitive dye, Organoid, medicine, Animals, MESH: Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, chemistry.chemical_classification, intestinal stem cells, Reactive oxygen species, MESH: Oxidative Stress, medicine.diagnostic_test, General Immunology and Microbiology, Cell growth, Chemistry, General Neuroscience, MESH: Reactive Oxygen Species, Cell biology, [SDV] Life Sciences [q-bio], Intestines, Organoids, fluorogenic probes, Oxidative Stress, Second messenger system, ROS detection, Stem cell, Reactive Oxygen Species, Oxidation-Reduction, Oxidative stress, MESH: Intestines
Abstract

Reactive oxygen species (ROS) play essential roles in intestinal homeostasis. ROS are natural by-products of cell metabolism. They are produced in response to infection or injury at the mucosal level as they are involved in antimicrobial responses and wound healing. They are also critical secondary messengers, regulating several pathways, including cell growth and differentiation. On the other hand, excessive ROS levels lead to oxidative stress, which can be deleterious for cells and favor intestinal diseases like chronic inflammation or cancer. This work provides a straightforward method to detect ROS in the intestinal murine organoids by live imaging and flow cytometry, using a commercially available fluorogenic probe. Here the protocol describes assaying the effect of compounds that modulate the redox balance in intestinal organoids and detect ROS levels in specific intestinal cell types, exemplified here by the analysis of the intestinal stem cells genetically labeled with GFP. This protocol may be used with other fluorescent probes.

Published
2021

46. Pleiotropic Effects of the P5-Type ATPase SpfA on Stress Response Networks Contribute to Virulence in the Pathogenic Mold Aspergillus fumigatus

Author

Ginés Luengo-Gil, Shivani Reddy, David S. Askew, Laura A. Woollett, Vishukumar Aimanianda, Sarah Sze Wah Wong, José P. Guirao-Abad, Nikita Malev, Christina Grisham, Martin Weichert, University of Cincinnati College of Medicine, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by National Institutes of Health (NIH) grant R01 AI123158-01A1 to D.S.A. and a University of Cincinnati Department of Pathology and Laboratory Medicine pilot research grant to J.P.G.-A.

Subjects
Male, MESH: Signal Transduction, Protein Folding, ATPase, UPR, sterols, Moths, MESH: Virulence, Endoplasmic Reticulum, medicine.disease_cause, Aspergillus fumigatus, Gene Knockout Techniques, Mice, HacA, MESH: Endoplasmic Reticulum Stress, Protein targeting, lipid metabolism, MESH: Sequence Analysis, RNA, Homeostasis, MESH: Animals, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Gene Knockout Techniques, Adenosine Triphosphatases, Virulence, biology, MESH: Moths, Spf1, Endoplasmic Reticulum Stress, QR1-502, Cell biology, MESH: Homeostasis, Larva, Female, MESH: Fungal Proteins, MESH: Aspergillus fumigatus, ER stress, Research Article, Signal Transduction, P5-type ATPases, MESH: Protein Folding, Microbiology, Fungal Proteins, redox balance, MESH: Endoplasmic Reticulum, Virology, SERCA, medicine, MESH: Adenosine Triphosphatases, Animals, SpfA, Secretion, MESH: Mice, Secretory pathway, redox homeostasis, Sequence Analysis, RNA, Endoplasmic reticulum, fungi, biology.organism_classification, MESH: Male, lipid homeostasis, biology.protein, Unfolded protein response, cell wall, MESH: Female, MESH: Larva
Abstract

International audience; Aspergillus fumigatus is a human-pathogenic mold that extracts nutrients from the environment or from host tissues by secreting hydrolytic enzymes. The ability of A. fumigatus to adjust secretion levels in proportion to demand relies on the assistance of the unfolded protein response (UPR), an adaptive stress response pathway that regulates the unique protein-folding environment of the endoplasmic reticulum (ER). The P5-type ATPase Spf1 has recently been implicated in a novel mechanism of ER homeostasis that involves correcting errors in ER-membrane protein targeting. However, the contribution of this protein to the biology of A. fumigatus is unknown. Here, we employed a gene knockout and RNA sequencing strategy to determine the functional role of the A. fumigatus gene coding for the orthologous P5 ATPase SpfA. The data reveal that the spfA gene is induced by ER stress in a UPR-dependent manner. In the absence of spfA, the A. fumigatus transcriptome shifts toward a profile of altered redox and lipid balance, in addition to a signature of ER stress that includes srcA, encoding a second P-type ATPase in the ER. A ΔspfA deletion mutant showed increased sensitivity to ER stress, oxidative stress, and antifungal drugs that target the cell wall or plasma membrane. The combined loss of spfA and srcA exacerbated these phenotypes and attenuated virulence in two animal infection models. These findings demonstrate that the ER-resident ATPases SpfA and SrcA act jointly to support diverse adaptive functions of the ER that are necessary for fitness in the host environment.IMPORTANCE The fungal UPR is an adaptive signaling pathway in the ER that buffers fluctuations in ER stress but also serves as a virulence regulatory hub in species of pathogenic fungi that rely on secretory pathway homeostasis for pathogenicity. This study demonstrates that the gene encoding the ER-localized P5-type ATPase SpfA is a downstream target of the UPR in the pathogenic mold A. fumigatus and that it works together with a second ER-localized P-type ATPase, SrcA, to support ER homeostasis, oxidative stress resistance, susceptibility to antifungal drugs, and virulence of A. fumigatus.

Published
2021

47. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

Author

Amanda Swain, Alexandre Gallerand, Judith C. Sluimer, François Orange, Erik A.L. Biessen, Alexia Castiglione, Inna Gaisler-Salomon, Stefania Carobbio, Laurent Yvan-Charvet, Rodolphe Guinamard, Thierry Berton, Julie Gall, Johanna Merlin, Stephen Rayport, Alexey Sergushichev, Jean-Charles Martin, Marion I. Stunault, Maxim N. Artyomov, Adélie Dumont, Edward B. Thorp, Marion Ayrault, Emmanuel L. Gautier, Justine Masson, Stoyan Ivanov, Pierre Maechler, Nathalie Vaillant, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), ITMO University [Russia], Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), The institute of cancer research [London], Université Côte d'Azur (UCA), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Genève = University of Geneva (UNIGE), The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] (CAM), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), The New York State Psychiatric Institute (NYSPI), Columbia University [New York], University of Haifa [Haifa], Washington University School of Medicine [Saint Louis, MO], Centre Commun de Microscopie Appliquée [Nice] (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Northwestern University [Chicago, Ill. USA], RWTH Aachen University, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Northwestern University Medical School [Chicago], Pathologie, RS: Carim - B07 The vulnerable plaque: makers and markers, and Gautier, Emmanuel

Subjects
EXPRESSION, PROMOTES, Endocrinology, Diabetes and Metabolism, Glutamine, [SDV]Life Sciences [q-bio], Cellular detoxification, Oxidative phosphorylation, METABOLISM, MOUSE, Oxidative Phosphorylation, Apoptotic cell clearance, 03 medical and health sciences, Mice, 0302 clinical medicine, MITOCHONDRIA, Phagocytosis, MESH: Oxidative Phosphorylation, Physiology (medical), Internal Medicine, Macrophage, Animals, MESH: Animals, CELL, Efferocytosis, ddc:612, MESH: Phagocytosis, ELECTRON-TRANSPORT, MESH: Mice, Tissue homeostasis, 030304 developmental biology, Amination, MESH: Amination, 0303 health sciences, MESH: Glutamine, Glutaminolysis, Chemistry, Cell Biology, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030217 neurology & neurosurgery
Abstract

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans. Merlin et al. find that non-canonical glutamine transamination is required for macrophage efferocytosis in atherosclerotic plaques by sustaining redox buffering and fueling energy production for cytoskeletal rearrangements.

Published
2021

48. Meiotic Behavior of Achiasmate Sex Chromosomes in the African Pygmy Mouse Mus mattheyi Offers New Insights into the Evolution of Sex Chromosome Pairing and Segregation in Mammals

Author

Ana Gil-Fernández, Marta Martín-Ruiz, Frédéric Veyrunes, Alberto Viera, Tamara Laguna, María Teresa Parra, Rocío Gómez, Pablo López-Jiménez, Marta Ribagorda, Jesús Page, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, UAM. Departamento de Biología, Universidad Autónoma de Madrid (UAM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), This research was funded by Grant CGL2014-53106-P from Ministerio de Economía yCompetitividad (Spain), French National Research Agency (ANR grant SEXREV 18-CE02-0018-01),Del Duca Foundation from the Institut de France ('subvention scientifique'). A.G.-F. was supportedby a predoctoral fellowship from the Ministerio de Economía y Competitividad (Spain) and theEuropean Social Fund (European Commission). M.R. was supported by a postgraduate grant fromDepartamento de Biología, Universidad Autónoma de Madrid (Spain)., and ANR-18-CE02-0018,SEXREV,Ménage à trois: un troisième chromosome sexuel féminisant. Conséquences évolutives et implications pour la génétique du déterminisme du sexe chez les mammifères(2018)

Subjects
Male, pygmy mouse, Pseudoautosomal region, Mus mattheyi, QH426-470, Mice, 0302 clinical medicine, Chromosome Segregation, meiosis, MESH: Animals, MESH: Chromosome Segregation / genetics, MESH: Evolution, Molecular, Genetics (clinical), Mammals, 0303 health sciences, Sex Chromosomes, Synapsis, MESH: Karyotype, MESH: Chromosome Pairing / genetics, Biología y Biomedicina / Biología, Meiosis, Female, Karyotype, Biology, Y chromosome, Evolution, Molecular, 03 medical and health sciences, evolution, Genetics, Animals, MESH: Mice, Metaphase, 030304 developmental biology, MESH: Sex Chromosomes / physiology, Autosome, sex chromosomes, Chromosome, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, MESH: Meiosis / genetics, MESH: Mammals / genetics, MESH: Male, Synaptonemal complex assembly, Chromosome Pairing, MESH: Karyotyping, Evolutionary biology, Karyotyping, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; X and Y chromosomes in mammals are different in size and gene content due to an evolutionary process of differentiation and degeneration of the Y chromosome. Nevertheless, these chromosomes usually share a small region of homology, the pseudoautosomal region (PAR), which allows them to perform a partial synapsis and undergo reciprocal recombination during meiosis, which ensures their segregation. However, in some mammalian species the PAR has been lost, which challenges the pairing and segregation of sex chromosomes in meiosis. The African pygmy mouse Mus mattheyi shows completely differentiated sex chromosomes, representing an uncommon evolutionary situation among mouse species. We have performed a detailed analysis of the location of proteins involved in synaptonemal complex assembly (SYCP3), recombination (RPA, RAD51 and MLH1) and sex chromosome inactivation (γH2AX) in this species. We found that neither synapsis nor chiasmata are found between sex chromosomes and their pairing is notably delayed compared to autosomes. Interestingly, the Y chromosome only incorporates RPA and RAD51 in a reduced fraction of spermatocytes, indicating a particular DNA repair dynamic on this chromosome. The analysis of segregation revealed that sex chromosomes are associated until metaphase-I just by a chromatin contact. Unexpectedly, both sex chromosomes remain labelled with γH2AX during first meiotic division. This chromatin contact is probably enough to maintain sex chromosome association up to anaphase-I and, therefore, could be relevant to ensure their reductional segregation. The results presented suggest that the regulation of both DNA repair and epigenetic modifications in the sex chromosomes can have a great impact on the divergence of sex chromosomes and their proper transmission, widening our understanding on the relationship between meiosis and the evolution of sex chromosomes in mammals.

Published
2021
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49. MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair

Author

de Krijger, Inge, Föhr, Bastian, Pérez, Santiago Hernández, Vincendeau, Estelle, Serrat, Judit, Thouin, Alexander Marc, Susvirkar, Vivek, Lescale, Chloé, Paniagua, Inés, Hoekman, Liesbeth, Kaur, Simranjeet, Altelaar, Maarten, Deriano, Ludovic, Faesen, Alex C, Jacobs, Jacqueline J L, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du système immunitaire (Inserm U1223), Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University [Utrecht], This work was supported by project grant 10999/2017-1 from the Dutch Cancer Society (KWF) to J.J.L.J., by the Institut Pasteur to L.D., by the Institut National Du Cancer (INCA_13852) to L.D., by the Ligue Nationale Contre le Cancer (Equipe labellisée 2019) to L.D. The Proteomics Facility of the Netherlands Cancer Institute was supported by the X-omics Initiative, partially funded by the Dutch Research Council (NWO)(project 184.034.019). E.V. received funding from Université de Paris, Sorbonne Paris Cité. A.C.F. is grateful for generous core funding by the Max Planck Society., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Lescale, Chloé

Subjects
DNA Repair, Chemistry(all), ATPase, MESH: DNA Breaks, Double-Stranded, Gene Expression, General Physics and Astronomy, Cell Cycle Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Piperazines, MESH: Recombinant Proteins, Mice, chemistry.chemical_compound, 0302 clinical medicine, DNA Breaks, Double-Stranded, MESH: Animals, 0303 health sciences, Multidisciplinary, biology, Chemistry, MESH: Protein Multimerization, DNA damage and repair, MESH: DNA, Recombinant Proteins, 3. Good health, Cell biology, DNA-Binding Proteins, MESH: ATPases Associated with Diverse Cellular Activities, MESH: HEK293 Cells, Mad2 Proteins, MESH: Phthalazines, MESH: Mad2 Proteins, Protein Binding, MESH: Cell Line, Tumor, MESH: Gene Expression, DNA repair, Science, Physics and Astronomy(all), Article, Chromosomes, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, MESH: Cell Cycle Proteins, Cell Line, Tumor, Animals, Humans, MESH: Protein Binding, Protein Interaction Domains and Motifs, MESH: Mice, 030304 developmental biology, MESH: Protein Interaction Domains and Motifs, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, MESH: Humans, TRIP13, Biochemistry, Genetics and Molecular Biology(all), [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, General Chemistry, DNA Repair Pathway, Fibroblasts, MESH: Cell Line, HEK293 Cells, MESH: Binding Sites, MESH: Cisplatin, MESH: Fibroblasts, MESH: HeLa Cells, biology.protein, ATPases Associated with Diverse Cellular Activities, Phthalazines, Cisplatin, Protein Multimerization, 030217 neurology & neurosurgery, Function (biology), MESH: DNA-Binding Proteins, HeLa Cells, Genetics and Molecular Biology(all)
Abstract

MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization-surface, HORMA-domain protein MAD2L2 has the extraordinary ability to wrap its C-terminus around SHLD3, likely creating a very stable complex. We show that appropriate function of MAD2L2 within shieldin requires its dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction. Dimerization-defective MAD2L2 impairs shieldin assembly and fails to promote NHEJ. Moreover, MAD2L2 dimerization, along with the presence of SHLD3, allows shieldin to interact with the TRIP13 ATPase, known to drive topological switches in HORMA-domain proteins. We find that appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair. Together our data provide important insights in the dependencies for shieldin activity., MAD2L2 — a member of the shieldin complex — is known to play important roles in DNA repair. Here the authors demonstrate how MAD2L2 dimerization mediated through SHLD2 participates in shieldin assembly and function.

Published
2021

50. Purification and Characterization of Bot33: A Non-Toxic Peptide from the Venom of Buthus occitanus tunetanus Scorpion

Author

Rym ElFessi, Oussema Khamessi, Najet Srairi-Abid, Jean-Marc Sabatier, Jan Tytgat, Steve Peigneur, Riadh Kharrat, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
potassium channel–Kv, [SDV]Life Sciences [q-bio], Scorpion Venoms, Pharmaceutical Science, MESH: Amino Acid Sequence, Analytical Chemistry, Scorpions, Mice, MESH: Scorpion Venoms, Drug Discovery, MESH: Molecular Docking Simulation, Animals, MESH: Animals, Amino Acid Sequence, Physical and Theoretical Chemistry, MESH: Mice, MESH: Peptides, Organic Chemistry, scorpion venom, voltage-dependent potassium channel, MESH: Scorpions, Molecular Docking Simulation, Chemistry (miscellaneous), Molecular Medicine, Peptides
Abstract

Scorpion venom is a rich source of promising therapeutic compounds, such as highly selective ion channel ligands with potent pharmacological effects. Bot33 is a new short polypeptide of 38 amino acid residues with six cysteines purified from the venom of the Buthus occitanus tunetanus scorpion. Bot33 has revealed less than 40% identity with other known alpha-KTx families. This peptide displayed a neutral amino acid (Leucine), in the position equivalent to lysine 27, described as essential for the interaction with Kv channels. Bot33 did not show any toxicity following i.c.v. injection until 2 µg/kg mouse body weight. Due to its very low venom concentration (0.24%), Bot33 was chemically synthesized. Unexpectedly, this peptide has been subjected to a screening on ion channels expressed in Xenopus laevis oocytes, and it was found that Bot33 has no effect on seven Kv channel subtypes. Interestingly, an in silico molecular docking study shows that the Leu27 prevents the interaction of Bot33 with the Kv1.3 channel. All our results indicate that Bot33 may have a different mode of action from other scorpion toxins, which will be interesting to elucidate. ispartof: MOLECULES vol:27 issue:21 ispartof: location:Switzerland status: published

Published
2022

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