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1. The Activation of the RIG-I/MDA5 Signaling Pathway upon Influenza D Virus Infection Impairs the Pulmonary Proinflammatory Response Triggered by Mycoplasma bovis Superinfection

Author

Maria Gaudino, Adrien Lion, Eveline Sagné, Brandy Nagamine, Justine Oliva, Olivier Terrier, Elisabeth Errazuriz-Cerda, Anaëlle Scribe, Fatima-Zohra Sikht, Elisa Simon, Charlotte Foret-Lucas, Blandine Gausserès, Julie Lion, Ana Moreno, Emilie Dordet-Frisoni, Eric Baranowski, Romain Volmer, Mariette F. Ducatez, Gilles Meyer, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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)-École normale supérieure de Lyon (ENS de Lyon)-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), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna 'Bruno Ubertini' (IZSLER), Innovations Thérapeutiques et Résistances (InTheRes), This study was funded by the by the Ecole Nationale Veterinaire de Toulouse (ENVT), project BQR-2020-ANIMEX, and the ICRAD-ERA NET cofund ANR-21-ICRD-0007, 'Deciphering the role of influenza D virus in bovine and human respiratory diseases in Europe.' Maria Gaudino was supported by a Ph.D. scholarship funded by the Departement Sante Animale (INRAE Toulouse) and the Region Occitanie. Maria Gaudino, Adrien Lion, Justine Oliva, Olivier Terrier, Fatima-Zohra Sikht, Romain Volmer, Gilles Meyer, and Mariette F. Ducatez are members of the French research network on influenza viruses (ResaFlu, GDR2073) financed by the CNRS., and ANR-21-ICRD-0007,PREVENTER,Deciphering the role of influenza D virus in bovine and human respiratory diseases in Europe(2021)

Subjects
coinfections, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, PCLS, cattle, Virology, Insect Science, respiratory viruses, Immunology, ex vivo, precision-cut lung slices, mycoplasma, influenza, Microbiology
Abstract

International audience; Concurrent infections with multiple pathogens are often described in cattle with respiratory illness. However, how the host-pathogen interactions influence the clinical outcome has been only partially explored in this species. Influenza D virus (IDV) was discovered in 2011. Since then, IDV has been detected worldwide in different hosts. A significant association between IDV and bacterial pathogens in sick cattle was shown in epidemiological studies, especially with Mycoplasma bovis. In an experimental challenge, IDV aggravated M. bovis-induced pneumonia. However, the mechanisms through which IDV drives an increased susceptibility to bacterial superinfections remain unknown. Here, we used the organotypic lung model precision-cut lung slices to study the interplay between IDV and M. bovis coinfection. Our results show that a primary IDV infection promotes M. bovis superinfection by increasing the bacterial replication and the ultrastructural damages in lung pneumocytes. In our model, IDV impaired the innate immune response triggered by M. bovis by decreasing the expression of several proinflammatory cytokines and chemokines that are important for immune cell recruitment and the bacterial clearance. Stimulations with agonists of cytosolic helicases and Toll-like receptors (TLRs) revealed that a primary activation of RIG-I/MDA5 desensitizes the TLR2 activation, similar to what was observed with IDV infection. The cross talk between these two pattern recognition receptors leads to a nonadditive response, which alters the TLR2-mediated cascade that controls the bacterial infection. These results highlight innate immune mechanisms that were not described for cattle so far and improve our understanding of the bovine host-microbe interactions and IDV pathogenesis.IMPORTANCE: Since the spread of the respiratory influenza D virus (IDV) infection to the cattle population, the question about the impact of this virus on bovine respiratory disease (BRD) remains still unanswered. Animals affected by BRD are often coinfected with multiple pathogens, especially viruses and bacteria. In particular, viruses are suspected to enhance secondary bacterial superinfections. Here, we use an ex vivo model of lung tissue to study the effects of IDV infection on bacterial superinfections. Our results show that IDV increases the susceptibility to the respiratory pathogen Mycoplasma bovis. In particular, IDV seems to activate immune pathways that inhibit the innate immune response against the bacteria. This may allow M. bovis to increase its proliferation and to delay its clearance from lung tissue. These results suggest that IDV could have a negative impact on the respiratory pathology of cattle.

Published
2023

2. Profiling of ob/ob mice skeletal muscle exosome-like vesicles demonstrates combined action of miRNAs, proteins and lipids to modulate lipid homeostasis in recipient cells

Author

Sophie Rome, Myriam Aouadi, Karim Bouzakri, Laura Reininger, Emmanuelle Berger, Emmanuelle Meugnier, Alexis Forterre, Alain Géloën, Jennifer Rieusset, Elizabeth Errazuriz-Cerda, Yohann Couté, Audrey Jalabert, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Diabète et thérapies cellulaires (DIATHEC), Université de Strasbourg (UNISTRA), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Université de Lyon, Karolinska Inst, Ctr Infect Med, Dept Med, Huddinge, Sweden, ANR-10-INBS-08, ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Diabète et thérapeutique : îlots pancréatiques et innovations technologiques (DIATHEC), and Diabète et thérapies cellulaires

Subjects
Male, Proteome, Science, Adipose tissue, Mice, Obese, Muscle Proteins, Exosomes, Exosome, Biochemistry, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Lipid oxidation, medicine, Myocyte, Animals, Homeostasis, Muscle, Skeletal, Beta oxidation, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Molecular medicine, Chemistry, Skeletal muscle, Lipid metabolism, Lipids, Cell biology, Mice, Inbred C57BL, MicroRNAs, Muscular Atrophy, medicine.anatomical_structure, Adipose Tissue, Medicine, Insulin Resistance, Sphingomyelin, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

We have determined the lipid, protein and miRNA composition of skeletal muscle (SkM)-released extracellular vesicles (ELVs) from Ob/ob (OB) vs wild-type (WT) mice. The results showed that atrophic insulin-resistant OB-SkM released less ELVs than WT-SkM, highlighted by a RAB35 decrease and an increase in intramuscular cholesterol content. Proteomic analyses of OB-ELVs revealed a group of 37 proteins functionally connected, involved in lipid oxidation and with catalytic activities. OB-ELVs had modified contents for phosphatidylcholine (PC 34-4, PC 40-3 and PC 34-0), sphingomyelin (Sm d18:1/18:1) and ceramides (Cer d18:1/18:0) and were enriched in cholesterol, likely to alleviated intracellular accumulation. Surprisingly many ELV miRNAs had a nuclear addressing sequence, and targeted genes encoding proteins with nuclear activities. Interestingly, SkM-ELV miRNA did not target mitochondria. The most significant function targeted by the 7 miRNAs altered in OB-ELVs was lipid metabolism. In agreement, OB-ELVs induced lipid storage in recipient adipocytes and increased lipid up-take and fatty acid oxidation in recipient muscle cells. In addition, OB-ELVs altered insulin-sensitivity and induced atrophy in muscle cells, reproducing the phenotype of the releasing OB muscles. These data suggest for the first time, a cross-talk between muscle cells and adipocytes, through the SkM-ELV route, in favor of adipose tissue expansion.

Published
2021

3. Rapeseed Lecithin Increases Lymphatic Lipid Output and α-Linolenic Acid Bioavailability in Rats

Author

Chloé Robert, Charline Buisson, Laurence Fonseca, Elisabeth Errazuriz-Cerda, Carole Vaysse, Emmanuelle Meugnier, Leslie Couëdelo, Emmanuelle Loizon, Marie-Caroline Michalski, Carole Knibbe, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Equipe Nutrition, Santé et Biochimie des Lipides (ITERG), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2), Université de Lyon, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, food.ingredient, 030309 nutrition & dietetics, Medicine (miscellaneous), Biological Availability, Lecithin, Microsomal triglyceride transfer protein, 03 medical and health sciences, food, Internal medicine, Lecithins, lipid metabolism, medicine, Animals, emulsifier, Carnitine, 030304 developmental biology, 0303 health sciences, Nutrition and Dietetics, biology, Chemistry, Brassica napus, Lipid metabolism, Bioavailability, Rats, alpha-linolenic acid, Endocrinology, Postprandial, nutrition, lecithin, biology.protein, Lymph, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], medicine.drug, Chylomicron
Abstract

International audience; Background: Soybean lecithin, a plant-based emulsifier widely used in food, is capable of modulating postprandial lipid metabolism. With arising concerns of sustainability, alternative sources of vegetal lecithin are urgently needed, and their metabolic effects must be characterized.Objectives: We evaluated the impact of increasing doses of rapeseed lecithin (RL), rich in essential alpha-linolenic acid (ALA), on postprandial lipid metabolism and ALA bioavailability in lymph-cannulated rats.Methods: Male Wistar rats (8 weeks old) undergoing a mesenteric lymph duct cannulation were intragastrically administered 1 g of an oil mixture containing 4% ALA and 0, 1, 3, 10, or 30% RL (5 groups). Lymph fractions were collected for 6 h. Lymph lipids and chylomicrons (CMs) were characterized. The expression of genes implicated in intestinal lipid metabolism was determined in the duodenum at 6 h. Data was analyzed using either sigmoidal or linear mixed-effects models, or one-way ANOVA, where appropriate.Results: RL dose-dependently increased the lymphatic recovery (AUC) of total lipids (1100 mu g/mL.h per additional RL%; P = 0.010) and ALA (50 mu g/mL.h per additional RL%; P = 0.0076). RL induced a faster appearance of ALA in lymph, as evidenced by the exponential decrease of the rate of appearance of ALA with RL (R-2 = 0.26; P= 0.0064). Although the number of CMs was unaffected by RL, CM diameter was increased in the 30%-RL group, compared to the control group (0% RL), by 86% at 3-4 h (P = 0.065) and by 81% at 4-6 h (P = 0.0002) following administration. This increase was positively correlated with the duodenal mRNA expression of microsomal triglyceride transfer protein (Mttp; rho= 0.63; P= 0.0052). The expression of Mttp and secretion-associated, ras-related GTPase 1 gene homolog B (Sarl b, CM secretion), carnitine palmitoyltransferase IA (Cpt1a) and acyl-coenzyme A oxidase 1 (Acoxl, beta-oxidation), and fatty acid desaturase 2 (Fads2, bioconversion of ALA into long-chain n-3 PUFAs) were, respectively, 49%, 29%, 74%, 48%, and 55% higher in the 30%-RL group vs. the control group (P < 0.05).Conclusions: In rats, RL enhanced lymphatic lipid output, as well as the rate of appearance of ALA, which may promote its subsequent bioavailability and metabolic fate.

Published
2020

4. Differential effect of glucose on ER-mitochondria Ca(2+) exchange participates to insulin secretion and to glucotoxicity-mediated dysfunction of beta cells

Author

Jennifer Rieusset, Charles Thivolet, Baptiste Panthu, Karim Chikh, Yves Gouriou, Elisabeth Errazuriz-Cerda, Florian Dingreville, Fabien Van Coppenolle, Marie-Agnes Chauvin, Sandra Pesenti, Sylvie Ducreux, A.-M. Madec, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Sante et de la Recherche Medicale (Inserm), French Ministry of Higher Education and Research, and JDRF award [31-2008-416]

Subjects
0301 basic medicine, Calcium metabolism, Chemistry, Endocrinology, Diabetes and Metabolism, Endoplasmic reticulum, Pancreatic islets, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Mitochondrion, 16. Peace & justice, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Organelle, Internal Medicine, Unfolded protein response, medicine, Glucose homeostasis, Mitochondrial fission
Abstract

Glucotoxicity-induced beta cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in beta cells is still largely unknown and their implication in glucotoxicity-associated beta cell dysfunction remains to be defined. Here, we report that acute glucose stimulation stimulated ER-mitochondria interactions and calcium (Ca(2+)) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS, and concomitantly reduced ER Ca(2+) store, increased basal mitochondrial Ca(2+) and reduced ATP-stimulated ER-mitochondria Ca(2+) exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca(2+) signaling are associated with ER stress, altered mitochondrial respiration and mitochondria fragmentation, and these organelle stresses may participate to increased organelle tethering, as a protective mechanism. Lastly, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca(2+) exchange, induced mitochondrial fission and altered GSIS. Therefore, dynamic organelle coupling participates to GSIS in beta cells and over-time disruption of organelle Ca(2+) exchange might be a novel mechanism contributing to glucotoxicity-induced beta cell dysfunction.

Published
2019

5. Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report

Author

Laurent Juillard, Maud Rabeyrin, Marine Panaye, Fitsum Guebre-Egziabher, Philippe Petiot, Sandrine Lemoine, Elisabeth Errazuriz-Cerda, Bénédicte Mousson de Camaret, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service Néphrologie Dialyse, Hypertension Arterielle, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service des Maladies Héréditaires du Métabolisme, Centre de Biologie et de pathologie Est-Hospices Civils de Lyon (HCL), Hôpital de la Croix-Rousse [CHU - HCL], Centre Hospitalier Universitaire [Grenoble] (CHU), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hospices Civils de Lyon (HCL)-Centre de Biologie et de pathologie Est

Subjects
Male, Pathology, medicine.medical_specialty, Ataxia, Adolescent, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Kearns-Sayre Syndrome, Gene mutation, Young Adult, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Renal Dialysis, Retinitis pigmentosa, medicine, Humans, Genetic Predisposition to Disease, Child, Myopathy, Dialysis, ComputingMilieux_MISCELLANEOUS, Kidney, Psychomotor retardation, medicine.diagnostic_test, business.industry, Biopsy, Needle, Mitochondrial Myopathies, Mitochondrial Proton-Translocating ATPases, medicine.disease, Immunohistochemistry, 3. Good health, Treatment Outcome, medicine.anatomical_structure, Nephrology, Disease Progression, Kidney Diseases, Renal biopsy, medicine.symptom, business, Retinitis Pigmentosa, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

We report a case of a patient who had the mitochondrial cytopathy complex of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome diagnosed at age 11 years with a biopsy-proven kidney involvement that progressed to end-stage renal disease at age 21 years. Mutations of mitochondrial DNA (mtDNA) are maternally inherited and lead to mitochondrial cytopathies with predominant neurologic manifestations: psychomotor retardation, epilepsy, ataxia, neuropathy, and myopathy. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. Mutations in the MT-ATP6 gene of mtDNA have been shown to cause NARP syndrome without renal involvement. We report a patient who had NARP syndrome diagnosed at age 11 years in whom glomerular proteinuria was present very early after diagnosis. Although neurologic manifestations were stable over time, he developed worsening proteinuria and kidney function. He started dialysis therapy at age 21 years. Kidney biopsy confirmed the mitochondrial cytopathy histologically, with abnormal mitochondria seen on electron microscopy. The MT-ATP6 gene mutation was detected in the kidney biopsy specimen.

Published
2018

6. B Cells Loaded with Synthetic Particulate Antigens: A Versatile Platform To Generate Antigen-Specific Helper T Cells for Cell Therapy

Author

Elisabeth Errazuriz-Cerda, Emmanuel Morelon, Angeline Rouers, Valérie Dubois, Olivier Thaunat, Thierry Defrance, Dimitri Chartoire, Stéphanie Graff-Dubois, Pascal Blanc, Morgan Taillardet, Sébastien Dussurgey, Antoine Sicard, Helena Paidassi, Arnaud Moris, Alice Koenig, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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)-École normale supérieure de Lyon (ENS de Lyon)-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), Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SFR Biosciences, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etablissement français du sang- Rhône-Alpes [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Endosome, Helper-Inducer, T-Lymphocytes, Adoptive, bioengineered nanoparticle, Cell- and Tissue-Based Therapy, Bioengineering, Nanotechnology, Lymphocyte Activation, Immunotherapy, Adoptive, antigen-presenting cell, Cell therapy, 03 medical and health sciences, CD4+ T cell, Antigen, medicine, Humans, General Materials Science, Antigen-presenting cell, Gene, B cell, Vaccines, Synthetic, B-Lymphocytes, Vaccines, Effector, Chemistry, Mechanical Engineering, Synthetic, General Chemistry, T-Lymphocytes, Helper-Inducer, biomimetic, Condensed Matter Physics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Polyclonal B cell response, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Nanoparticles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, cell therapy
Abstract

International audience; Adoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators.

Published
2016

7. Platelet activation and aggregation promote lung inflammation and influenza virus pathogenesis

Author

Jochen G. Schneider, Jean-Luc Guérin, Vuong Ba Lê, Bruno Lina, Iris Adrian, Elisabeth Errazuriz-Cerda, Béatrice Riteau, Jean-Claude Bordet, Fatma Berri, Stephan Ludwig, Sonia Frasquilho, Martine Jandrot-Perrus, Mariette F. Ducatez, Laurent Antunes, Yvonne Boergeling, Virologie et pathologie humaine (VirPath), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Saarland University [Saarbrücken], Université du Luxembourg (Uni.lu), University of Münster, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Lyon, Integrated BioBank of Luxembourg (IBBL), Centre Hospitalier Universitaire de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR (HemoFlu) [ANR-13-BSV3-0011], DFG [SCH682/3-1], EU [CIG303682], FNR CORE Itgb3Vascln, Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group) [research center], ProdInra, Migration, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
Male, Platelet Aggregation, [SDV]Life Sciences [q-bio], Anti-Inflammatory Agents, 030204 cardiovascular system & hematology, Biochemistry, biophysics & molecular biology [F05] [Life sciences], flu pathogenesis, Critical Care and Intensive Care Medicine, medicine.disease_cause, Anti-Inflammatory Agents/therapeutic use, Platelet Activation/physiology, Pathogenesis, Mice, 0302 clinical medicine, Influenza A virus, Medicine, Platelet, Orthomyxoviridae/drug effects/pathogenicity, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], Antiviral Agents/therapeutic use, 0303 health sciences, Mice, Inbred BALB C, novel drugs, biology, virus diseases, Orthomyxoviridae, Pneumonia/complications/drug therapy/physiopathology, 3. Good health, [SDV] Life Sciences [q-bio], platelets, Female, medicine.symptom, Pulmonary and Respiratory Medicine, Inflammation, Lung injury, Influenza, Human/complications/drug therapy/physiopathology/virology, Antiviral Agents, Virus, 03 medical and health sciences, Platelet Aggregation/physiology, Influenza, Human, Animals, Humans, pneumonia, Platelet activation, lung injury, 030304 developmental biology, business.industry, biology.organism_classification, Platelet Activation, Virology, Disease Models, Animal, Immunology, business
Abstract

International audience; Rationale: The hallmark of Severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. Objectives: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza. Methods: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza virus infection in mice. Measurements and Main Results: Lungs of infected mice were Massively infiltrated by aggregates of activated platelets. Platelet activation promoted influenza A virus pathogenesis. Activating protease-activated receptor 4, a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa protected mice from death caused by influenza viruses, and treating the mice with a specific glycoprotein IIb/IIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other antiplatelet compounds (antagonists of protease-activated receptor 4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains. Conclusions: The intricate relationship between hemostasis and inflammation has major consequences in influenza virus pathogenesis, and antiplatelet drugs might be explored to develop new antiinflammatory treatment against influenza virus infections.

Published
2015

8. Myotube-derived exosomal miRNAs downregulate Sirtuin1 in myoblasts during muscle cell differentiation

Author

Etienne Lefai, Audrey Jalabert, Hubert Vidal, Sophie Rome, Sandra Pesenti, Karim Chikh, Elizabeth Errazuriz, Vanessa Euthine, Alexis Forterre, Aurélie Granjon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Fondation pour la Recherche Medicale (FRM ), Association Francaise de recherche sur les Myopathies (AFM ), Association Francaise de Diabetologie (SDF ), INRA-specific grant (ANSSD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
MicroRNAs/*biosynthesis/classification/genetics, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Biology, Skeletal/metabolism, Exosomes, Exosome, Muscle Fibers, Myoblasts, 03 medical and health sciences, Mice, 0302 clinical medicine, Report, medicine, Cell Differentiation/*genetics, Sirtuins, Myocyte, Animals, Homeostasis, Sirtuins/*biosynthesis/genetics, Developmental, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, 0303 health sciences, Myogenesis, Muscle cell differentiation, Wnt signaling pathway, Gene Expression Regulation, Developmental, Skeletal muscle, Cell Differentiation, Cell Biology, Microvesicles, Cell biology, MicroRNAs, Exosomes/metabolism, medicine.anatomical_structure, Gene Expression Regulation, 030220 oncology & carcinogenesis, Muscle, Myoblasts/cytology/*metabolism, Skeletal/growth & development/metabolism, C2C12, Developmental Biology
Abstract

International audience; It has recently been established that exosomes can mediate intercellular cross-talk under normal and pathological conditions through the transfer of specific miRNAs. As muscle cells secrete exosomes, we addressed the question of whether skeletal muscle (SkM) exosomes contained specific miRNAs, and whether they could act as "endocrine signals" during myogenesis. We compared the miRNA repertoires found in exosomes released from C2C12 myoblasts and myotubes and found that 171 and 182 miRNAs were exported into exosomes from myoblasts and myotubes, respectively. Interestingly, some miRNAs were expressed at higher levels in exosomes than in their donor cells and vice versa, indicating a selectivity in the incorporation of miRNAs into exosomes. Moreover miRNAs from C2C12 exosomes were regulated during myogenesis. The predicted target genes of regulated exosomal miRNAs are mainly involved in the control of important signaling pathways for muscle cell differentiation (e.g., Wnt signaling pathway). We demonstrated that exosomes from myotubes can transfer small RNAs (C. elegans miRNAs and siRNA) into myoblasts. Moreover, we present evidence that exosome miRNAs secreted by myotubes are functionally able to silence Sirt1 in myoblasts. As Sirt1 regulates muscle gene expression and differentiation, our results show that myotube-exosome miRNAs could contribute to the commitment of myoblasts in the process of differentiation. Until now, myokines in muscle cell secretome provided a conceptual basis for communication between muscles. Here, we show that miRNA exosomal transfer would be a powerful means by which gene expression is orchestrated to regulate SkM metabolic homeostasis.

Published
2014

9. Proteomic analysis of C2C12 myoblast and myotube exosome-like vesicles: a new paradigm for myoblast-myotube cross talk?

Author

Joffrey De Larichaudy, Anne-Marie Hesse, Stéphanie Chanon, Elisabeth Errazuriz, Sophie Rome, Yohann Couté, Mathieu Baudet, Michèle Weiss-Gayet, Etienne Lefai, Michel Record, Alexis Forterre, Emmanuelle Berger, Alain Géloën, Hubert Vidal, Karim Chikh, Audrey Jalabert, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Fondation pour la Recherche Medicale (FRM), Association Francaise de recherche sur les Myopathies (AFM), Association Francaise de Diabetologie (SDF/Rochediagnostics France), and INRA specific grant (ANSSD)

Subjects
Proteomics, Myoblast proliferation, Integrins, Anatomy and Physiology, Proteome, Skeletal/*metabolism, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Exosomes, Cell-Derived Microparticles/metabolism/ultrastructure, Biochemistry, Myoblasts, Mice, 0302 clinical medicine, Cell-Derived Microparticles, Molecular Cell Biology, Morphogenesis, Musculoskeletal System, 0303 health sciences, Multidisciplinary, Myogenesis, Proteomic Databases, Cell Differentiation, Exosomes/*metabolism/ultrastructure, Transport protein, Cell biology, Extracellular Matrix, Protein Transport, 030220 oncology & carcinogenesis, Cytochemistry, Muscle, Medicine, Cellular Types, Information Technology, C2C12, Research Article, Endosome, Science, Biology, Exosome, Muscle Fibers, Proteomics/methods, Cell Line, 03 medical and health sciences, Databases, Cell Adhesion, Animals, 030304 developmental biology, Cell Proliferation, Muscle Cells, Microvesicles, Membrane protein, Computer Science, Skeletal Development, Myoblasts/cytology/*metabolism, Developmental Biology
Abstract

International audience; Exosomes are nanometer-sized microvesicles formed in multivesicular bodies (MVBs) during endosome maturation. Exosomes are released from cells into the microenvironment following fusion of MVBs with the plasma membrane. During the last decade, skeletal muscle-secreted proteins have been identified with important roles in intercellular communications. To investigate whether muscle-derived exosomes participate in this molecular dialog, we determined and compared the protein contents of the exosome-like vesicles (ELVs) released from C2C12 murine myoblasts during proliferation (ELV-MB), and after differentiation into myotubes (ELV-MT). Using a proteomic approach combined with electron microscopy, western-blot and bioinformatic analyses, we compared the protein repertoires within ELV-MB and ELV-MT. We found that these vesicles displayed the classical properties of exosomes isolated from other cell types containing components of the ESCRT machinery of the MVBs, as well as numerous tetraspanins. Specific muscle proteins were also identified confirming that ELV composition also reflects their muscle origin. Furthermore quantitative analysis revealed stage-preferred expression of 31 and 78 proteins in ELV-MB and ELV-MT respectively. We found that myotube-secreted ELVs, but not ELV-MB, reduced myoblast proliferation and induced differentiation, through, respectively, the down-regulation of Cyclin D1 and the up-regulation of myogenin. We also present evidence that proteins from ELV-MT can be incorporated into myoblasts by using the GFP protein as cargo within ELV-MT. Taken together, our data provide a useful database of proteins from C2C12-released ELVs throughout myogenesis and reveals the importance of exosome-like vesicles in skeletal muscle biology.

Published
2014

10. Characterization of a Novel Type of HIV-1 Particle Assembly Inhibitor Using a Quantitative Luciferase-Vpr Packaging-Based Assay

Author

Gonzalez, Gaëlle, DaFonseca, Sandrina, Errazuriz, Elisabeth, Coric, Pascale, Souquet, Florence, Turcaud, Serge, Boulanger, Pierre, Bouaziz, Serge, Hong, Saw See, Major, Eugene Oliver, Centre de recherche, CHU Montréal, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Université de Lyon-Université de Lyon, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), This work has been supported by the French AIDS foundation (SIDACTION-contract A/19-3-01541) and the Agence Nationale de Recherche sur le SIDA (ANRS, Grant DendrAde 2007-2008). SDF was the recipient of an ANRS fellowship, and GG was the recipient of a fellowship from the French Foundation for Cystic Fibrosis (Vaincre la Mucoviscidose). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Bouaziz, Serge, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), HONG, Saw-See, and Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE)

Subjects
multidisciplinary sciences, viruses, lcsh:Medicine, Sf9, MESH: vpr Gene Products, Human Immunodeficiency Virus, law.invention, MESH: HIV-1, chemistry.chemical_compound, law, Betulinic acid, Nanotechnology, MESH: Animals, lcsh:Science, Cytotoxicity, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, MESH: Spodoptera, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 030302 biochemistry & molecular biology, vpr Gene Products, Human Immunodeficiency Virus, Antivirals, inhibitor, retrovirus, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Recombinant DNA, Medicine, Infectious diseases, MESH: Virion, Electrophoresis, Polyacrylamide Gel, Research Article, Biotechnology, science and technology, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Materials Science, Retrovirology and HIV immunopathogenesis, Viral diseases, MESH: Microscopy, Electron, Viral Structure, Spodoptera, Microbiology, Material by Attribute, Cell Line, 03 medical and health sciences, Virology, Viruslike Particles, Extracellular, Animals, Luciferase, Biology, Nanomaterials, HIV-1, virus-like, 030304 developmental biology, lcsh:R, Virion, HIV, Molecular biology, MESH: Cell Line, Microscopy, Electron, Enzyme, chemistry, Cell culture, Bionanotechnology, Biophysics, lcsh:Q, MESH: Electrophoresis, Polyacrylamide Gel
Abstract

International audience; The HIV-1 auxiliary protein Vpr and Vpr-fusion proteins can be copackaged with Gag precursor (Pr55Gag) into virions or membrane-enveloped virus-like particles (VLP). Taking advantage of this property, we developed a simple and sensitive method to evaluate potential inhibitors of HIV-1 assembly in a living cell system. Two proteins were coexpressed in recombinant baculovirus-infected Sf9 cells, Pr55Gag, which formed the VLP backbone, and luciferase fused to the N-terminus of Vpr (LucVpr). VLP-encapsidated LucVpr retained the enzymatic activity of free luciferase. The levels of luciferase activity present in the pelletable fraction recovered from the culture medium correlated with the amounts of extracellular VLP released by Sf9 cells assayed by conventional immunological methods. Our luciferase-based assay was then applied to the characterization of betulinic acid (BA) derivatives that differed from the leader compound PA-457 (or DSB) by their substituant on carbon-28. The beta-alanine-conjugated and lysine-conjugated DSB could not be evaluated for their antiviral potentials due to their high cytotoxicity, whereas two other compounds with a lesser cytotoxicity, glycine-conjugated and ε-NH-Boc-lysine-conjugated DSB, exerted a dose-dependent negative effect on VLP assembly and budding. A fifth compound with a low cytotoxicity, EP-39 (ethylene diamine-conjugated DSB), showed a novel type of antiviral effect. EP-39 provoked an aberrant assembly of VLP, resulting in nonenveloped, morula-like particles of 100-nm in diameter. Each morula was composed of nanoparticle subunits of 20-nm in diameter, which possibly mimicked transient intermediates of the HIV-1 Gag assembly process. Chemical cross-linking in situ suggested that EP-39 favored the formation or/and persistence of Pr55Gag trimers over other oligomeric species. EP-39 showed a novel type of negative effect on HIV-1 assembly, targeting the Pr55Gag oligomerisation. The biological effect of EP-39 underlined the critical role of the nature of the side chain at position 28 of BA derivatives in their anti-HIV-1 activity.

Published
2011

11. Long-term propagation of serum hepatitis C virus (HCV) with production of enveloped HCV particles in human HepaRG hepatocytes

Author

Pascale Berthillon, Marie-Anne Petit, Isabelle Bordes, Elisabeth Errazuriz, Christian Trepo, Sylvie De Sequeira, Ndiémé Ndongo-Thiam, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie et de gastroentérologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-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), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cell Differentiation, medicine.medical_specialty, Time Factors, Apolipoprotein B, medicine.drug_class, Cellular differentiation, Hepatitis C virus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepacivirus, MESH: Stem Cells, Monoclonal antibody, medicine.disease_cause, MESH: Hepatocytes, 03 medical and health sciences, 0302 clinical medicine, Viral Envelope Proteins, Antigen, Internal medicine, medicine, Humans, MESH: Hepacivirus, Progenitor cell, Cells, Cultured, 030304 developmental biology, MESH: Hepatitis C, 0303 health sciences, MESH: Humans, Hepatology, biology, Stem Cells, MESH: Time Factors, Virion, Cell Differentiation, Hepatitis C, Virology, In vitro, 3. Good health, MESH: Viral Envelope Proteins, Hepatocytes, biology.protein, MESH: Virion, 030211 gastroenterology & hepatology, MESH: Cells, Cultured
Abstract

International audience; UNLABELLED: HepaRG human liver progenitor cells exhibit morphology and functionality of adult hepatocytes. We investigated the susceptibility of HepaRG hepatocytes to in vitro infection with serum-derived hepatitis C virus (HCV) particles (HCVsp) and the potential neutralizing activity of the E1E2-specific monoclonal antibody (mAb) D32.10. The infection was performed using HCVsp when the cells actively divided at day 3 postplating. HCV RNA, E1E2, and core antigens were quantified in HCV particles recovered from culture supernatants of differentiated cells for up to 66 days. The density distributions of particles were analyzed on iodixanol or sucrose gradients. Electron microscopy (EM) and immune-EM studies were performed for ultrastructural analysis of cells and localization of HCV E1E2 proteins in thin sections. HCV infection of HepaRG cells was documented by increasing production of E1E2-core-RNA(+) HCV particles from day 21 to day 63. Infectious particles sedimented between 1.06 and 1.12 g/mL in iodixanol gradients. E1E2 and core antigens were expressed in 50% of HCV-infected cells at day 31. The D32.10 mAb strongly inhibited HCV RNA production in HepaRG culture supernatants. Infected HepaRG cells frozen at day 56 were reseeded at low density. After only 1-3 subcultures and induction of a cell differentiation process the HepaRG cells produced high titer HCV RNA and thus showed to be sustainably infected. Apolipoprotein B-associated empty E1E2 and complete HCV particles were secreted. Characteristic virus-induced intracellular membrane changes and E1E2 protein-association to vesicles were observed. CONCLUSION: HepaRG progenitor cells permit HCVsp infection. Differentiated HepaRG cells support long-term production of infectious lipoprotein-associated enveloped HCV particles. The E1E2-specific D32.10 mAb neutralizes the infection and this cellular model could be used as a surrogate infection system for the screening of entry inhibitors.

Published
2011

12. Photocatalysis and disinfection of water: Identification of potential bacterial targets

Author

Elisabeth Errazuriz-Cerda, F. Simonet, S. Pigeot-Rémy, D. Atlan, J. C. Lazzaroni, Chantal Guillard, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Microorganism, 02 engineering and technology, 010501 environmental sciences, medicine.disease_cause, 01 natural sciences, Catalysis, chemistry.chemical_compound, medicine, Escherichia coli, 0105 earth and related environmental sciences, General Environmental Science, Growth medium, biology, Chemistry, Process Chemistry and Technology, [CHIM.CATA]Chemical Sciences/Catalysis, 021001 nanoscience & nanotechnology, biology.organism_classification, Enterobacteriaceae, [SDE.ES]Environmental Sciences/Environmental and Society, 6. Clean water, Biochemistry, Biophysics, Photocatalysis, Nucleic acid, 0210 nano-technology, Bacterial outer membrane, Bacteria
Abstract

3-4 Pigeot-Remy, S. Simonet, F. Errazuriz-Cerda, E. Lazzaroni, J. C. Atlan, D. Guillard, C.; In order to identify some of the potential bacterial targets, the effects of TiO2 nanoparticles on bacteria in aqueous suspension were assessed in the dark and under UV-A (lambda > 340 nm) radiation exposure, using the microorganism model Escherichia coli K-12. Illumination was produced with a HPK 125W lamp and suspended TiO2 Degussa P-25 was used as the photocatalyst, absorbing all the incident UV-A radiations. The impact of the photocatalyst on the bacteria was investigated by monitoring cell cultivability, cell wall integrity and nucleic acid stability. The contact of TiO2 particles with bacteria in the dark increased the bacterial sensitivity to membrane-perturbing agents, suggesting an increase in outer membrane permeability. In contrast, the contact between SiO2 particles, with an average particle size similar to that of TiO2 P-25, and bacteria did not induce any alteration of the cell permeability. The TiO2 deleterious action on the envelope integrity continued during the UV-A radiations exposure. Impacts on bacterial permeability precede the total loss of cultivability. After 2.5 h of photocatalytic treatment at 3.45 mW/cm(2), bacteria were no longer cultivable on their standard growth medium. However, some of them could become cultivable again under specific environmental conditions appropriate to their survival. These resilient bacteria exposed again to UV-A photocatalysis were more resistant to the treatment. Some chemical by-products released during photocatalytic inactivation of the bacteria were also monitored. The appearance of oxamic and oxalic acids as well as ammonium cations, sulfate and nitrate anions were observed. Transmission electron microscopy (TEM) was used to study the morphological damages to E. coli structure during the photocatalytic inactivation of the microorganisms. After 1.5 h of treatment, bacteria showed disorganized membrane structures, while bacteria were still visible although they were no longer cultivable after a longer exposure time. These results were correlated with damages of nucleic acids at in vivo level. An analysis by electrophoresis revealed that bacterial DNA and RNA molecules completely disappeared after 7 h of photocatalytic treatment. (C) 2011 Published by Elsevier B.V.

Published
2011

13. Photocatalysis and disinfection of water

Author

Pigeot-Remy, S., Simonet, F., Errazuriz-Cerda, E., Lazzaroni, J. C., Atlan, D., Guillard, C., Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Département de Physique Théorique et Appliquée (DPTA), DAM Île-de-France (DAM/DIF), Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[CHIM.CATA]Chemical Sciences/Catalysis, [SDE.ES]Environmental Sciences/Environmental and Society
Abstract

international

Published
2010

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