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6. Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1

Author

Vabret, Nicolas, Najburg, Valérie, Solovyov, Alexander, Gopal, Ramya, McClain, Christopher, Šulc, Petr, Balan, Sreekumar, Rahou, Yannis, Beauclair, Guillaume, Chazal, Maxime, Varet, Hugo, Legendre, Rachel, Sismeiro, Odile, Sanchez David, Raul Y., Chauveau, Lise, Jouvenet, Nolwenn, Markowitz, Martin, van der Werf, Sylvie, Schwartz, Olivier, Tangy, Frédéric, Bhardwaj, Nina, Greenbaum, Benjamin D., and Komarova, Anastassia V.

Published
2022
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12. SIV-induced terminally differentiated adaptive NK cells in lymph nodes associated with enhanced MHC-E restricted activity

Author

Huot, Nicolas, Rascle, Philippe, Petitdemange, Caroline, Contreras, Vanessa, Stürzel, Christina M., Baquero, Eduard, Harper, Justin L., Passaes, Caroline, Legendre, Rachel, Varet, Hugo, Madec, Yoann, Sauermann, Ulrike, Stahl-Hennig, Christiane, Nattermann, Jacob, Saez-Cirion, Asier, Le Grand, Roger, Keith Reeves, R., Paiardini, Mirko, Kirchhoff, Frank, Jacquelin, Beatrice, and Müller-Trutwin, Michaela

Published
2021
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14. Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis

Author

de Castro, Raffael Júnio Araújo, primary, Marina, Clara Luna, additional, Sturny-Leclère, Aude, additional, Hoffmann, Christian, additional, Bürgel, Pedro Henrique, additional, Wong, Sarah Sze Wah, additional, Aimanianda, Vishukumar, additional, Varet, Hugo, additional, Agrawal, Ruchi, additional, Bocca, Anamélia Lorenzetti, additional, and Alanio, Alexandre, additional

Published
2023
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15. Inhibition of the macrophage demethylase LSD1 reverses Leishmania amazonensis-induced transcriptomic changes and causes a decrease in parasite load

Author

Gutierrez-Sanchez, Maria, primary, Zhang, Sheng, additional, Gharsallah, Charfeddine, additional, Lamotte, Suzanne, additional, Varet, Hugo, additional, Legendre, Rachel, additional, Dingli, Florent, additional, Loew, Damarys, additional, Rotili, Dante, additional, Valente, Sergio, additional, Mai, Antonello, additional, Loiseau, Philippe, additional, Pomel, Sebastien, additional, Jung, Manfred, additional, Lecoeur, Herve, additional, Prina, Eric, additional, and Spaeth, Gerald Frank, additional

Published
2023
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20. Transcriptome profiling of human col\onic cells exposed to the gut pathobiont Streptococcus gallolyticus subsp. gallolyticus.

Author

Pasquereau-Kotula, Ewa, du Merle, Laurence, Sismeiro, Odile, Pietrosemoli, Natalia, Varet, Hugo, Legendre, Rachel, Trieu-Cuot, Patrick, and Dramsi, Shaynoor

Subjects
STREPTOCOCCUS, TRANSCRIPTOMES, CANCER genes, ENDOPLASMIC reticulum
Abstract

Streptococcus gallolyticus sp. gallolyticus (SGG) is a gut pathobiont involved in the development of colorectal cancer (CRC). To decipher SGG contribution in tumor initiation and/or acceleration respectively, a global transcriptome was performed in human normal colonic cells (FHC) and in human tumoral colonic cells (HT29). To identify SGG-specific alterations, we chose the phylogenetically closest relative, Streptococcus gallolyticus subsp. macedonicus (SGM) as control bacterium. We show that SGM, a bacterium generally considered as safe, did not induce any transcriptional changes on the two human colonic cells. The transcriptional reprogramming induced by SGG in normal FHC and tumoral HT29 cells was significantly different, although most of the genes up- and down-regulated were associated with cancer disease. Top up-regulated genes related to cancer were: (i) IL-20, CLK1, SORBS2, ERG1, PIM1, SNORD3A for normal FHC cells and (ii) TSLP, BHLHA15, LAMP3, ZNF27B, KRT17, ATF3 for cancerous HT29 cells. The total number of altered genes were much higher in cancerous than in normal colonic cells (2,090 vs 128 genes being affected, respectively). Gene set enrichment analysis reveals that SGG-induced strong ER- (endoplasmic reticulum) stress and UPR- (unfolded protein response) activation in colonic epithelial cells. Our results suggest that SGG induces a pro-tumoral shift in human colonic cells particularly in transformed cells potentially accelerating tumor development in the colon. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Immunometabolic profiling ofin vitroandex vivo Leishmania-infected macrophages (LIMs) reveals unique polarization and bioenergetic signatures

Author

Zhang, Sheng, primary, Lecoeur, Hervé, additional, Varet, Hugo, additional, Legendre, Rachel, additional, Mahtal, Nassim, additional, Proux, Caroline, additional, Aulner, Nathalie, additional, Shorte, Spencer, additional, Granjean, Capucine, additional, Bousso, Philippe, additional, Prina, Eric, additional, and Späth, Gerald F., additional

Published
2022
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28. CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

Author

Huot, Nicolas, Rascle, Philippe, Planchais, Cyril, Contreras, Vanessa, Passaes, Caroline, Le Grand, Roger, Beignon, Anne-Sophie, Kornobis, Etienne, Legendre, Rachel, Varet, Hugo, Saez-Cirion, Asier, Mouquet, Hugo, Jacquelin, Beatrice, Müller-Trutwin, Michaela, HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), For sequencing and analysis support, we thank the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA. NH was supported by the Fondation Jacquelin Beytout and Institut Pasteur. PR was recipient of a PhD fellowship from the University Paris Diderot, Sorbonne Paris Cité and also supportedby the NIH (R01AI143457). CP was the recipient of a PhD fellowship from the ANRS. HM received core grants from the Institut Pasteur, the INSERM and the Milieu Intérieur Program(ANR-10-LABX-69-01). We would like to acknowledge funding support from ANRS, MSDAvenir and Institut Pasteur to MM-Tand AS-C. We gratefully acknowledge the support to IDMIT from the French government: Investments for the Future program for infrastructures (PIA) through the ANR-11-INBS-0008 grant as well as from the PIA grant ANR-10-EQPX-02-01 to the FlowCyTech facility at IDMIT., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), ANR-10-EQPX-0002,FlowCyTech,Plateforme de phénotypage en Mass cytométrie pour l'analyse multiparamétrique de biomarqueurs complexes de l'efficacité de nouvelles stratégies thérapeutiques ou vaccinales(2010), HIV, Inflammation et persistance, Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Varet, Hugo, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, and Equipements d'excellence - Plateforme de phénotypage en Mass cytométrie pour l'analyse multiparamétrique de biomarqueurs complexes de l'efficacité de nouvelles stratégies thérapeutiques ou vaccinales - - FlowCyTech2010 - ANR-10-EQPX-0002 - EQPX - VALID

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, HIV, CD4, LN, [SDV] Life Sciences [q-bio], SIV, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, natural host, Immunology and Allergy, CD32, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD20, intestine
Abstract

International audience; CD4 T cell responses constitute an important component of adaptive immunity and are critical regulators of anti-microbial protection. CD4 + T cells expressing CD32a have been identified as a target for HIV. CD32a is an Fcγ receptor known to be expressed on myeloid cells, granulocytes, B cells and NK cells. Little is known about the biology of CD32 + CD4 + T cells. Our goal was to understand the dynamics of CD32 + CD4 + T cells in tissues. We analyzed these cells in the blood, lymph nodes, spleen, ileum, jejunum and liver of two nonhuman primate models frequently used in biomedical research: African green monkeys (AGM) and macaques. We studied them in healthy animals and during viral (SIV) infection. We performed phenotypic and transcriptomic analysis at different stages of infection. In addition, we compared CD32+CD4+ T cells in tissues with well-controlled (spleen) and not efficiently controlled (jejunum) SIV replication in AGM. The CD32 + CD4 + T cells more frequently expressed markers associated with T cell activation and HIV infection (CCR5, PD-1, CXCR5, CXCR3) and had higher levels of actively transcribed SIV RNA than CD32 - CD4 + T cells. Furthermore, CD32 + CD4 + T cells from lymphoid tissues strongly expressed B-cell-related transcriptomic signatures, and displayed B cell markers at the cell surface, including immunoglobulins CD32+CD4+ T cells were rare in healthy animals and blood but increased strongly in tissues with ongoing viral replication. CD32 + CD4 + T cell levels in tissues correlated with viremia. Our results suggest that the tissue environment induced by SIV replication drives the accumulation of these unusual cells with enhanced susceptibility to viral infection.

Published
2021

29. Transcriptional adaptation of Mycobacterium ulcerans in an original mouse model: New insights into the regulation of mycolactone

Author

Robbe-Saule, Marie, Foulon, Mélanie, Poncin, Isabelle, Esnault, Lucille, Varet, Hugo, Legendre, Rachel, Besnard, Alban, Grzegorzewicz, Anna, Jackson, Mary, Canaan, Stéphane, Marsollier, Laurent, Marion, Estelle, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Aix Marseille Université (AMU), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Mycobacteria Research Laboratories [Fort Collins, CO, États-Unis], Department of Microbiology, Immunology and Pathology [Fort Collins, CO, États-Unis], Colorado State University [Fort Collins] (CSU)-Colorado State University [Fort Collins] (CSU), This work was supported by the Agence Nationale de la Recherche [Grant ANR-15-IFEC-0006], Agence Nationale de la Recherche [Grant ANR- 16-CE12-0023], Fondation pour la Recherche Médicale [Equipe FRM], Region Pays de la Loire [Grant Starter], Fondation Raoul Follereau, INSERM., ANR-15-IFEC-0006,BU_SPONT_HEAL,Transcriptome Analysis of Animal Models of Spontaneous Healing of Buruli Ulcer(2015), ANR-16-CE12-0023,MYCOPARADOX,Dissection de l'architecture génétique des réactions paradoxales dans la Lèpre et l'Ulcère de Buruli(2016), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut Pasteur [Paris], ATOMycA (CRCINA-ÉQUIPE 6), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Pasteur [Paris], Colorado State University [Fort Collins] (CSU), Varet, Hugo, Transcriptome Analysis of Animal Models of Spontaneous Healing of Buruli Ulcer - - BU_SPONT_HEAL2015 - ANR-15-IFEC-0006 - Infect-ERA - VALID, and Dissection de l'architecture génétique des réactions paradoxales dans la Lèpre et l'Ulcère de Buruli - - MYCOPARADOX2016 - ANR-16-CE12-0023 - AAPG2016 - VALID

Subjects
Mycobacterium Infections, Mycobacterium ulcerans, [SDV]Life Sciences [q-bio], Adaptation, Biological, mycolactone, Infectious and parasitic diseases, RC109-216, Gene Expression Regulation, Bacterial, [SDV] Life Sciences [q-bio], Mice, host-bacterium interaction, Animals, Humans, rna-sequencing, Macrolides, Buruli Ulcer, metabolism, Research Article, Research Paper, rnasequencing
Abstract

We thank all members of the animal SCAHU platform.; International audience; Mycobacterium ulcerans is the causal agent of Buruli ulcer, a chronic infectious disease and the third most common mycobacterial disease worldwide. Without early treatment, M. ulcerans provokes massive skin ulcers, caused by the mycolactone toxin, its main virulence factor. However, spontaneous healing may occur in Buruli ulcer patients several months or years after the disease onset. We have shown, in an original mouse model, that bacterial load remains high and viable in spontaneously healed tissues, with a switch of M. ulcerans to low levels of mycolactone production, adapting its strategy to survive in such a hostile environment. This original model offers the possibility to investigate the regulation of mycolactone production, by using an RNA-seq strategy to study bacterial adaptation during mouse infection. Pathway analysis and characterization of the tissue environment showed that the bacillus adapted to its new environment by modifying its metabolic activity and switching nutrient sources. Thus, M. ulcerans ensures its survival in healing tissues by reducing its secondary metabolism, leading to an inhibition of mycolactone synthesis. These findings shed new light on mycolactone regulation and pave the way for new therapeutic strategies.

Published
2021

30. PDGFRα-induced stromal maturation is required to restrain postnatal intestinal epithelial stemness and promote defense mechanisms

Author

Jacob, Jean-Marie, primary, Di Carlo, Selene E., additional, Stzepourginski, Igor, additional, Lepelletier, Anthony, additional, Ndiaye, Papa Diogop, additional, Varet, Hugo, additional, Legendre, Rachel, additional, Kornobis, Etienne, additional, Benabid, Adam, additional, Nigro, Giulia, additional, and Peduto, Lucie, additional

Published
2022
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31. The gut environment regulates bacterial gene expression which modulates susceptibility to bacteriophage infection

Author

Lourenço, Marta, primary, Chaffringeon, Lorenzo, additional, Lamy-Besnier, Quentin, additional, Titécat, Marie, additional, Pédron, Thierry, additional, Sismeiro, Odile, additional, Legendre, Rachel, additional, Varet, Hugo, additional, Coppée, Jean-Yves, additional, Bérard, Marion, additional, De Sordi, Luisa, additional, and Debarbieux, Laurent, additional

Published
2022
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34. Experimental evolution links post-transcriptional regulation to Leishmania fitness gain

Author

Piel, Laura, primary, Rajan, K. Shanmugha, additional, Bussotti, Giovanni, additional, Varet, Hugo, additional, Legendre, Rachel, additional, Proux, Caroline, additional, Douché, Thibaut, additional, Giai-Gianetto, Quentin, additional, Chaze, Thibault, additional, Cokelaer, Thomas, additional, Vojtkova, Barbora, additional, Gordon-Bar, Nadav, additional, Doniger, Tirza, additional, Cohen-Chalamish, Smadar, additional, Rengaraj, Praveenkumar, additional, Besse, Céline, additional, Boland, Anne, additional, Sadlova, Jovana, additional, Deleuze, Jean-François, additional, Matondo, Mariette, additional, Unger, Ron, additional, Volf, Petr, additional, Michaeli, Shulamit, additional, Pescher, Pascale, additional, and Späth, Gerald F., additional

Published
2022
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35. Early Transcriptional Changes in Rabies Virus-Infected Neurons and Their Impact on Neuronal Functions

Author

Kim, Seonhee, Larrous, Florence, Varet, Hugo, Legendre, Rachel, Feige, Lena, Dumas, Guillaume, Matsas, Rebecca, Kouroupi, Georgia, Grailhe, Regis, Bourhy, Hervé, Institut Pasteur Korea - Institut Pasteur de Corée, Réseau International des Instituts Pasteur (RIIP), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], École Doctorale Bio Sorbonne Paris Cité [Paris] (ED BioSPC), Université Sorbonne Paris Cité (USPC)-Université de Paris (UP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biomics (plateforme technologique), Montreal Institute for Learning Algorithms [Montréal] (MILA), Centre de Recherches Mathématiques [Montréal] (CRM), Université de Montréal (UdeM)-Université de Montréal (UdeM), CHU Sainte Justine [Montréal], Institut Pasteur Hellénique, This work was supported by grants from Partenariat Hubert Curien (No. 41432ZB), Ministry of Science and ICT of Korea (Nos. 2017M3A9G6068257 and 2018K1A3A1A21041166), and internal fundings of Institut Pasteur., Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
calcium imaging, [SDV]Life Sciences [q-bio], matrix protein, early post-infection, neuronal dysfunction, rabies virus, Microbiology, transcriptome, Original Research
Abstract

International audience; Rabies is a zoonotic disease caused by rabies virus (RABV). As rabies advances, patients develop a variety of severe neurological symptoms that inevitably lead to coma and death. Unlike other neurotropic viruses that can induce symptoms of a similar range, RABV-infected post-mortem brains do not show significant signs of inflammation nor the structural damages on neurons. This suggests that the observed neurological symptoms possibly originate from dysfunctions of neurons. However, many aspects of neuronal dysfunctions in the context of RABV infection are only partially understood, and therefore require further investigation. In this study, we used differentiated neurons to characterize the RABV-induced transcriptomic changes at the early time-points of infection. We found that the genes modulated in response to the infection are particularly involved in cell cycle, gene expression, immune response, and neuronal function-associated processes. Comparing a wild-type RABV to a mutant virus harboring altered matrix proteins, we found that the RABV matrix protein plays an important role in the early down-regulation of host genes, of which a significant number is involved in neuronal functions. The kinetics of differentially expressed genes (DEGs) are also different between the wild type and mutant virus datasets. The number of modulated genes remained constant upon wild-type RABV infection up to 24 h post-infection, but dramatically increased in the mutant condition. This result suggests that the intact viral matrix protein is important to control the size of host gene modulation. We then examined the signaling pathways previously studied in relation to the innate immune responses against RABV, and found that these pathways contribute to the changes in neuronal function-associated processes. We further examined a set of regulated genes that could impact neuronal functions collectively, and demonstrated in calcium imaging that indeed the spontaneous activity of neurons is influenced by RABV infection. Overall, our findings suggest that neuronal function-associated genes are modulated by RABV early on, potentially through the viral matrix protein-interacting signaling molecules and their downstream pathways.

Published
2021

36. The oxidative stress response of pathogenic Leptospira is controlled by two peroxide stress regulators which putatively cooperate in controlling virulence

Author

Zavala-Alvarado, Crispin, G. Huete, Samuel, Vincent, Antony T., Sismeiro, Odile, Legendre, Rachel, Varet, Hugo, Bussotti, Giovanni, Lorioux, Céline, Lechat, Pierre, Coppée, Jean-Yves, Veyrier, Frédéric J., Picardeau, Mathieu, and Benaroudj, Nadia

Subjects
Models, Molecular, Virulence Factors, Pathology and Laboratory Medicine, Microbiology, Biochemistry, Regulon, Bacterial Proteins, Gene Types, Medicine and Health Sciences, Genetics, Gene Regulatory Networks, Leptospirosis, Amino Acid Sequence, Non-coding RNA, Gene Prediction, Microbial Pathogens, Phylogeny, Leptospira, Bacteria, Virulence, Organisms, Biology and Life Sciences, Computational Biology, Genomics, Gene Expression Regulation, Bacterial, Genome Analysis, Adaptation, Physiological, Bacterial Pathogens, Nucleic acids, Mutant Strains, Repressor Proteins, Leptospira Interrogans, Oxidative Stress, Medical Microbiology, Mutation, Regulator Genes, RNA, Pathogens, Sequence Alignment, Research Article
Abstract

Pathogenic Leptospira are the causative agents of leptospirosis, the most widespread zoonotic infectious disease. Leptospirosis is a potentially severe and life-threatening emerging disease with highest burden in sub-tropical areas and impoverished populations. Mechanisms allowing pathogenic Leptospira to survive inside a host and induce acute leptospirosis are not fully understood. The ability to resist deadly oxidants produced by the host during infection is pivotal for Leptospira virulence. We have previously shown that genes encoding defenses against oxidants in L. interrogans are repressed by PerRA (encoded by LIMLP_10155), a peroxide stress regulator of the Fur family. In this study, we describe the identification and characterization of another putative PerR-like regulator (LIMLP_05620) in L. interrogans. Protein sequence and phylogenetic analyses indicated that LIMLP_05620 displayed all the canonical PerR amino acid residues and is restricted to pathogenic Leptospira clades. We therefore named this PerR-like regulator PerRB. In L. interrogans, the PerRB regulon is distinct from that of PerRA. While a perRA mutant had a greater tolerance to peroxide, inactivating perRB led to a higher tolerance to superoxide, suggesting that these two regulators have a distinct function in the adaptation of L. interrogans to oxidative stress. The concomitant inactivation of perRA and perRB resulted in a higher tolerance to both peroxide and superoxide and, unlike the single mutants, a double perRAperRB mutant was avirulent. Interestingly, this correlated with major changes in gene and non-coding RNA expression. Notably, several virulence-associated genes (clpB, ligA/B, and lvrAB) were repressed. By obtaining a double mutant in a pathogenic Leptospira strain, our study has uncovered an interplay of two PerRs in the adaptation of Leptospira to oxidative stress with a putative role in virulence and pathogenicity, most likely through the transcriptional control of a complex regulatory network., Author summary Leptospirosis is a widespread infectious disease responsible for over one million of severe cases and 60 000 fatalities annually worldwide. This neglected and emerging disease has a worldwide distribution, but it mostly affects populations from developing countries in sub-tropical areas. The causative agents of leptospirosis are pathogenic bacterial Leptospira spp. There is a considerable deficit in our knowledge of these atypical bacteria, including their virulence mechanisms. In addition to the Leptospira PerRA regulator that represses defenses against peroxide, we have identified and characterized a second PerR regulator in pathogenic Leptospira species (PerRB) that participates in Leptospira tolerance to superoxide. Phenotypic and transcriptomic analyses of single PerRA and PerRB mutants suggest that the two PerRs fulfill distinct functions in the adaptation to oxidative stress. Concomitant inactivation of PerRA and PerRB resulted in a higher tolerance to both peroxide and superoxide. Moreover, the perRAperRB mutant lost its virulence. Major changes in gene expression, including a decreased expression of several virulence factors, were observed in the double perRAperRB mutant. Our study suggests that PerRA and PerRB cooperate to orchestrate a complex regulatory network involved in Leptospira virulence.

Published
2021

37. Trained ILC3 responses promote intestinal defense

Author

Serafini, Nicolas, primary, Jarade, Angélique, additional, Surace, Laura, additional, Goncalves, Pedro, additional, Sismeiro, Odile, additional, Varet, Hugo, additional, Legendre, Rachel, additional, Coppee, Jean-Yves, additional, Disson, Olivier, additional, Durum, Scott K., additional, Frankel, Gad, additional, and Di Santo, James P., additional

Published
2022
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39. HP1γ binding pre-mRNA intronic repeats modulates RNA splicing decisions

Author

Rachez, Christophe, Legendre, Rachel, Costallat, Mickaël, Varet, Hugo, Yi, Jia, Kornobis, Etienne, Muchardt, Christian, Régulation épigénétique - Epigenetic regulation, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), This work was supported by Institut National de la Santé et la Recherche Médicale (Inserm, C.R.), Centre National de la Recherche Scientifique (CNRS, C.M.), with grants from Institut Pasteur, Agence Nationale de la Recherche (ANR-11-BSV8–0013), Inserm Cancer (ITMO Cancer 20CN068-00) and Labex REVIVE - Investissements d’Avenir (to E.K. and C.M.). J.Y. is part of the Pasteur—Paris University (PPU) International PhD Program. This programme has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 665807., We are grateful to all members of the Epigenetic Regulation unit for helpful discussions, Madeleine Moscatelli and Cynthia Bezier for helpful preliminary experiments, Catherine Bodin for technical assistance and Edith Ollivier for administrative assistance. Thanks to Caroline Proux for her expertise in library preparation and Illumina sequencing and to Eric Batsché for critically reading the manuscript. We thank Jiuyong Xie for the gift of plasmids, ANR-11-BSV8-0013,iSPLICE,Régulation de l'épissage alternatif par la machinerie du RNAi(2011), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)

Subjects
HP1, [SDV]Life Sciences [q-bio], RNA Splicing, RNA-Binding Proteins, splicing Subject Categories Chromatin, Articles, RNA Biology, Introns, splicing, Alternative Splicing, Transcription & Genomics, Cbx3, RNA Precursors, RNA, chromatin
Abstract

International audience; HP1 proteins are best known as markers of heterochromatin and gene silencing. Yet, they are also RNA-binding proteins and the HP1c/CBX3 family member is present on transcribed genes together with RNA polymerase II, where it regulates cotranscriptional processes such as alternative splicing. To gain insight in the role of the RNA-binding activity of HP1c in transcriptionally active chromatin, we have captured and analysed RNAs associated with this protein. We find that HP1c is specifically targeted to hexameric RNA motifs and coincidentally transposable elements of the SINE family. As these elements are abundant in introns, while essentially absent from exons, the HP1c RNA association tethers unspliced pre-mRNA to chromatin via the intronic regions and limits the usage of intronic cryptic splice sites. Thus, our data unveil novel determinants in the relationship between chromatin and co-transcriptional splicing.

Published
2021

40. The oxidative stress response and virulence of pathogenic Leptospira are controlled by the interplay of two peroxide stress regulators

Author

Zavala-Alvarado, Crispin, Vincent, Antony, Sismeiro, Odile, Legendre, Rachel, Varet, Hugo, Bussotti, Giovanni, Lorioux, Céline, Coppée, Jean-Yves, Veyrier, Frédéric, Picardeau, Mathieu, Benaroudj, Nadia, Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris] (IP), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Biomics (plateforme technologique), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Crispin Zavala-Alvarado was part of the Pasteur-Paris University (PPU) International PhD Program. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 665807 and from Fondation Etchebès-Fondation France (S-CM 16008)., European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Leptospira, Spirochetes, [SDV]Life Sciences [q-bio], PerR, reactive oxygen species (ROS), Microbiology, RNASeq, virulence, oxidative stress, leptospirosis, non-coding RNAs, [INFO]Computer Science [cs], transcription regulation, Fur
Abstract

Pathogenic Leptospira are the causative agents of leptospirosis, the most widespread zoonotic infectious disease. Leptospirosis is a potentially severe and life-threatening emerging disease with highest burden in sub-tropical areas and impoverish populations. Mechanisms allowing pathogenic Leptospira to survive inside a host and induce acute leptospirosis are not fully understood. The ability to resist deadly oxidants produced by the host during infection is pivotal for Leptospira virulence. We have previously shown that genes encoding defenses against oxidants in L. interrogans are repressed by PerRA (encoded by LIMLP_10155), a peroxide stress regulator of the Fur family. In this study, we describe the identification and characterization of another putative PerR-like regulator (LIMLP_05620) in L. interrogans . Protein sequence and phylogenetic analyses indicated that LIMLP_05620 displayed all the canonical PerR amino acid residues and is restricted to pathogenic Leptospira clades. We therefore named this PerR-like regulator PerRB. In L. interrogans , the PerRB regulon is distinct from that of PerRA. While a perRA mutant had a greater tolerance to peroxide, inactivating perRB led to a higher tolerance to superoxide, suggesting that these two regulators have a distinct function in the adaptation of L. interrogans to oxidative stress. The concomitant inactivation of perRA and perRB resulted in a higher tolerance to both peroxide and superoxide and, unlike the single mutants, to the loss of Leptospira virulence. Interestingly, this correlated with major changes in gene and non-coding RNA expression, only observed in the double perRAperRB mutant. Notably, several virulence-associated genes ( clpB , ligA/B , and lvrAB ) were repressed. By obtaining the first double mutant in a pathogenic Leptospira strain, our study has uncovered for the first time the interplay of two PerRs, not only in the adaptation of Leptospira to oxidative stress, but also in their virulence and pathogenicity, most likely through the transcriptional control of a complex regulatory network.

Published
2021

41. Role of the major determinant of polar flagellation FlhG in the endoflagella‐containing spirochete Leptospira

Author

Fule, Lenka, primary, Halifa, Ruben, additional, Fontana, Celia, additional, Sismeiro, Odile, additional, Legendre, Rachel, additional, Varet, Hugo, additional, Coppée, Jean‐Yves, additional, Murray, Gerald L., additional, Adler, Ben, additional, Hendrixson, David R., additional, Buschiazzo, Alejandro, additional, Guo, Shuaiqi, additional, Liu, Jun, additional, and Picardeau, Mathieu, additional

Published
2021
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42. The CovR regulatory network drives the evolution of Group B Streptococcus virulence

Author

Mazzuoli, Maria-Vittoria, primary, Daunesse, Maëlle, additional, Varet, Hugo, additional, Rosinski-Chupin, Isabelle, additional, Legendre, Rachel, additional, Sismeiro, Odile, additional, Gominet, Myriam, additional, Kaminski, Pierre Alexandre, additional, Glaser, Philippe, additional, Chica, Claudia, additional, Trieu-Cuot, Patrick, additional, and Firon, Arnaud, additional

Published
2021
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43. Post-transcriptional regulation of Leishmania fitness gain

Author

PIEL, Laura, SHANMUGHA RAJAN, K., BUSSOTTI, Giovanni, VARET, Hugo, LEGENDRE, Rachel, PROUX, Caroline, DOUCHÉ, Thibaut, GIAI-GIANETTO, Quentin, CHAZE, Thibault, VOJTKOVA, Barbora, GORDON-BAR, Nadav, DONIGER, Tirza, COHEN-CHALAMISH, Smadar, RENGARAJ, Praveenkumar, BESSE, Céline, BOLAND, Anne, SADLOVA, Jovana, DELEUZE, Jean-François, MATONDO, Mariette, UNGER, Ron, VOLF, Petr, MICHAELI, Shulamit, PESCHER, Pascale, SPÄTH, Gerald, Parasitologie moléculaire et Signalisation / Molecular Parasitology and Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Bar-Ilan University [Israël], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biomics (plateforme technologique), Institut Pasteur [Paris], Plateforme de Protéomique / Proteomics platform, Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Charles University [Prague] (CU), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, This work was supported by the Fondation de la Recherche Médicale contract FDT201805005619(LP), the Agence Nationale pour la Recherche Labex ‘Integrative Biology of Emerging InfectiousDiseases’ contract ANR-10-LABX-62-IBEID and Labex ‘French Alliance for Parasitology and HealthCare’ contract ANR-11-LABX-0024 (GFS, LP, PP, GB), the Campus France Franco-Israeli ProgrammeHubert Curien Maimonide 2018 (GFS and SM), the seeding grant from the Institut Pasteur International Department to the LeiSHield Consortium and the EU H2020 project LeiSHield-MATI - REP-778298-1 (GB), the France Génomique National infrastructure, funded as part of the « Investissements d’Avenir » program managed by the Agence Nationale pour la Recherche contract ANR-10-INBS-09 (HV, RL, CP), and the ERD Funds, project CePaViP (CZ.02.1.01/0.0/0.0/ 16_019/0000759) (BV, JS, PV). We thank the CEA-CNRGH for its contribution to the sequencing costs and all the CEA-CNRGH staff who contributed to sample preparation and sequencing for their excellent technical assistance., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Bussotti, Giovanni, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], Leishmania, transcriptomics, posttranscriptional adaptation, [SDV]Life Sciences [q-bio], genomics, [INFO]Computer Science [cs], experimental evolution, [INFO] Computer Science [cs], small nucleolar RNAs, fitness
Abstract

The protozoan parasite Leishmania donovani causes fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network driving parasite fitness, with genome instability causing highly reproducible, gene dosage-dependent changes in protein linked to post-transcriptional regulation. These in turn were associated with a gene dosage-independent reduction in flagellar transcripts and a coordinated increase in abundance of coding and non-coding RNAs known to regulate ribosomal biogenesis and protein translation. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence that Leishmania fitness gain may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model for Leishmania fitness gain, where differential regulation of mRNA stability and the generation of fitness-adapted ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach to Leishmania epidemiology and identifies the Leishmania non-coding small RNome as a potential novel source for biomarker discovery.

Published
2021

45. Tissue damage induces a conserved stress response that initiates quiescent muscle stem cell activation

Author

Machado, Léo, primary, Geara, Perla, additional, Camps, Jordi, additional, Dos Santos, Matthieu, additional, Teixeira-Clerc, Fatima, additional, Van Herck, Jens, additional, Varet, Hugo, additional, Legendre, Rachel, additional, Pawlotsky, Jean-Michel, additional, Sampaolesi, Maurilio, additional, Voet, Thierry, additional, Maire, Pascal, additional, Relaix, Frederic, additional, and Mourikis, Philippos, additional

Published
2021
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46. Aspergillus fumigatus, One Uninucleate Species with Disparate Offspring

Author

Danion, François, van Rhijn, Norman van, Dufour, Alexandre C, Legendre, Rachel, Sismeiro, Odile, Varet, Hugo, Olivo-Marin, Jean-Christophe, Mouyna, Isabelle, Chamilos, Georgios, Bromley, Michael, Beauvais, Anne, Latgé, Jean-Paul, Aspergillus, Institut Pasteur [Paris] (IP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Strasbourg, Manchester Fungal Infection Group, Institute for Inflammation and Repair, University of Manchester [Manchester], Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, University of Crete [Heraklion] (UOC), This research was partly funded by the French national reference center for Primary Immunodeficiencies (CEREDIH, Hôpital Necker-Enfants Malades, Paris, France), grant 2017 and the APC was funded by CEREDIH. This research was also funded by la Fondation pour la Recherche Médicale (DEQ20150331722 LATGE Equipe FRM 2015)., Institut Pasteur [Paris], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Institut Pasteur [Paris]

Subjects
Aspergillus fumigatus, [SDV]Life Sciences [q-bio], fungi, conidium, Article, lcsh:Biology (General), germination, aspergillosis, asynchrony, skin and connective tissue diseases, lcsh:QH301-705.5, transcriptome, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Establishment of a fungal infection due to Aspergillus fumigatus relies on the efficient germination of the airborne conidia once they penetrate the respiratory tract. However, the features of conidial germination have been poorly explored and understood in this fungal species as well as in other species of filamentous fungi. We show here that the germination of A. fumigatus is asynchronous. If the nutritional environment and extensive gene deletions can modify the germination parameters for A. fumigatus, the asynchrony is maintained in all germinative conditions tested. Even though the causes for this asynchrony of conidial germination remain unknown, asynchrony is essential for the completion of the biological cycle of this filamentous fungus.

Published
2021

47. Queuine Is a Nutritional Regulator of Entamoeba histolytica Response to Oxidative Stress and a Virulence Attenuator

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Nagaraja, Shruti, Cai, Maggi W, Sun, Jingjing, Varet, Hugo, Sarid, Lotem, Trebicz-Geffen, Meirav, Shaulov, Yana, Mazumdar, Mohit, Legendre, Rachel, Coppée, Jean-Yves, Begley, Thomas J, Dedon, Peter C, Gourinath, Samudrala, Guillen, Nancy, Saito-Nakano, Yumiko, Shimokawa, Chikako, Hisaeda, Hajime, Ankri, Serge, Massachusetts Institute of Technology. Department of Biological Engineering, Nagaraja, Shruti, Cai, Maggi W, Sun, Jingjing, Varet, Hugo, Sarid, Lotem, Trebicz-Geffen, Meirav, Shaulov, Yana, Mazumdar, Mohit, Legendre, Rachel, Coppée, Jean-Yves, Begley, Thomas J, Dedon, Peter C, Gourinath, Samudrala, Guillen, Nancy, Saito-Nakano, Yumiko, Shimokawa, Chikako, Hisaeda, Hajime, and Ankri, Serge

Abstract

Queuosine is a naturally occurring modified ribonucleoside found in the first position of the anticodon of the transfer RNAs for Asp, Asn, His, and Tyr. Eukaryotes lack pathways to synthesize queuine, the nucleobase precursor to queuosine, and must obtain it from diet or gut microbiota. Here, we describe the effects of queuine on the physiology of the eukaryotic parasite Entamoeba histoly-tica, the causative agent of amebic dysentery. Queuine is efficiently incorporated into E. histolytica tRNAs by a tRNA-guanine transglycosylase (EhTGT) and this incorporation stimulates the methylation of C38 in tRNA GUC. Queuine protects the parasite against oxidative stress (OS) and antagonizes the negative effect that oxidation has on translation by inducing the expression of genes involved in the OS response, such as heat shock protein 70 (Hsp70), antioxidant enzymes, and enzymes involved in DNA repair. On the other hand, queuine impairs E. histolytica virulence by downregu-lating the expression of genes previously associated with virulence, including cysteine proteases, cytoskeletal proteins, and small GTPases. Silencing of EhTGT prevents incorporation of queuine into tRNAs and strongly impairs methylation of C38 in tRNA GUC, parasite growth, resistance to OS, and cytopathic activity. Overall, our data reveal that queuine plays a dual role in promoting OS resistance and reducing parasite virulence. IMPORTANCE Entamoeba histolytica is a unicellular parasite that causes amebiasis. The parasite resides in the colon and feeds on the colonic microbiota. The gut flora is implicated in the onset of symptomatic amebiasis due to alterations in the composition of bacteria. These bacteria modulate the physiology of the parasite and affect the virulence of the parasite through unknown mechanisms. Queuine, a modified nucleobase of queuosine, is exclusively produced by the gut bacteria and leads to tRNA modification at the anticodon loops of specific tRNAs. We found that queuine induces mil

Published
2021

48. Depletion of slow-cycling PDGFRα+ADAM12+mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis

Author

Di Carlo, Selene E., Raffenne, Jerome, Varet, Hugo, Ode, Anais, Granados, David Cabrerizo, Stein, Merle, Legendre, Rachel, Tuckermann, Jan, Bousquet, Corinne, and Peduto, Lucie

Abstract

The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12+PDGFRα+mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12+MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3and Csf1. Genetic depletion of ADAM12+cells restored a functional tumor vasculature, reduced hypoxia and acidosis and normalized CAFs, inducing infiltration of effector T cells and growth inhibition of melanomas and pancreatic neuroendocrine cancer, in a process dependent on TGF-β. In human cancer, ADAM12 stratifies patients with high levels of hypoxia and innate resistance mechanisms, as well as factors associated with a poor prognosis and drug resistance such as AXL. Altogether, our data show that depletion of tumor-induced slow-cycling PDGFRα+MSCs through ADAM12 restores antitumor immunity.

Published
2023
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50. Queuine Is a Nutritional Regulator of Entamoeba histolytica Response to Oxidative Stress and a Virulence Attenuator

Author

Nagaraja, Shruti, primary, Cai, Maggi W., additional, Sun, Jingjing, additional, Varet, Hugo, additional, Sarid, Lotem, additional, Trebicz-Geffen, Meirav, additional, Shaulov, Yana, additional, Mazumdar, Mohit, additional, Legendre, Rachel, additional, Coppée, Jean-Yves, additional, Begley, Thomas J., additional, Dedon, Peter C., additional, Gourinath, Samudrala, additional, Guillen, Nancy, additional, Saito-Nakano, Yumiko, additional, Shimokawa, Chikako, additional, Hisaeda, Hajime, additional, and Ankri, Serge, additional

Published
2021
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