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9 results on '"Elodie Décembre"'

1. Adaptation to host cell environment during experimental evolution of Zika virus

Author

Sara Munoz-Gonzalez, Coralie Guy, Elodie Décembre, Peter Markov, Bastien Boussau, Alain Kohl, Marlène Dreux, Mathilde Paris, Thomas Höfer, Kassian Kobert, Vincent Grass, Soheil Rastgou Talemi, Emilie Hardy, Anja Böckmann, Lee Sherry, Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, 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), Luxembourg Institute of Health (LIH), MRC - University of Glasgow Centre for Virus Research, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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), Le Cocon, Département PEGASE [LBBE] (PEGASE), 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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Grass, Vincent [0000-0001-7710-4789], Talemi, Soheil Rastgou [0000-0002-9999-2403], Décembre, Elodie [0000-0001-6891-6320], Kohl, Alain [0000-0002-1523-9458], Muñoz-González, Sara [0000-0002-7846-7001], Sherry, Lee [0000-0002-4367-772X], Höfer, Thomas [0000-0003-3560-8780], Boussau, Bastien [0000-0003-0776-4460], Dreux, Marlène [0000-0002-6607-4796], and Apollo - University of Cambridge Repository

Subjects
Infectivity, Experimental evolution, Zika Virus Infection, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Medicine (miscellaneous), Zika Virus, Biology, biology.organism_classification, Phenotype, Virology, Antiviral Agents, Virus, General Biochemistry, Genetics and Molecular Biology, Zika virus, Toll-Like Receptor 3, Viral replication, Interferon, Viral evolution, medicine, Humans, Interferons, General Agricultural and Biological Sciences, medicine.drug
Abstract

Zika virus (ZIKV) infection can cause developmental and neurological defects and represents a threat for human health. Type I/III interferon responses control ZIKV infection and pathological processes, yet the virus has evolved various mechanisms to defeat these host responses. Here, we established a pipeline to delineate at high-resolution the genetic evolution of ZIKV in a controlled host cell environment. We uncovered that serially passaged ZIKV acquired increased infectivity, defined as the probability for one virus to initiate infection, and simultaneously developed a resistance to TLR3-induced restriction. We built a mathematical model that suggests that the increased infectivity is due to a reduced time-lag between infection and viral replication. We found that this adaptation is cell-type specific, suggesting that different cell environments may drive viral evolution along different routes. Deep-sequencing of ZIKV quasi-species pinpointed mutations whose increased frequencies temporally coincide with the acquisition of the adapted phenotype. We functionally validated a point-mutation in ZIKV envelope (E) protein recapitulating the adapted phenotype. Its positioning on the E structure suggests a putative function in protein refolding/stability. Altogether, our results uncovered ZIKV adaptations to the cell environment leading to an accelerated replication onset coupled with resistance to TLR3-induced antiviral response. Our work provides insights into viral escape mechanisms and interactions with host cell and can serve as a framework to study other viruses.

Published
2020
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2. Plasmacytoid Dendritic Cells and Infected Cells Form an Interferogenic Synapse Required for Antiviral Responses

Author

Marlène Dreux, Séverin Coléon, Lee Sherry, Elodie Décembre, Congcong Dong, Brian Webster, Sonia Assil, Omran Allatif, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
Hepatitis C virus, [SDV]Life Sciences [q-bio], Endocytic cycle, Integrin, Hepacivirus, Dengue virus, medicine.disease_cause, Microbiology, Antiviral Agents, Virus, Cell Line, Synapse, 03 medical and health sciences, 0302 clinical medicine, Interferon, Virology, medicine, Cell Adhesion, Humans, Immunologic Factors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, hemic and immune systems, TLR7, Dendritic Cells, Zika Virus, Dengue Virus, Intercellular Adhesion Molecule-1, Coculture Techniques, Immunity, Innate, Lymphocyte Function-Associated Antigen-1, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Toll-Like Receptor 7, Virus Diseases, Interferon Type I, biology.protein, Parasitology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Type I interferon (IFN-I) is critical for antiviral defense, and plasmacytoid dendritic cells (pDCs) are a predominant source of IFN-I during virus infection. pDC-mediated antiviral responses are stimulated upon physical contact with infected cells, during which immunostimulatory viral RNA is transferred to pDCs, leading to IFN production via the nucleic acid sensor TLR7. Using dengue, hepatitis C, and Zika viruses, we demonstrate that the contact site of pDCs with infected cells is a specialized platform we term the interferogenic synapse, which enables viral RNA transfer and antiviral responses. This synapse is formed via αLβ2 integrin-ICAM-1 adhesion complexes and the recruitment of the actin network and endocytic machinery. TLR7 signaling in pDCs promotes interferogenic synapse establishment and provides feed-forward regulation, sustaining pDC contacts with infected cells. This interferogenic synapse may allow pDCs to scan infected cells and locally secrete IFN-I, thereby confining a potentially deleterious response.

Published
2019
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3. Immature particles and capsid-free viral RNA produced by Yellow fever virus-infected cells stimulate plasmacytoid dendritic cells to secrete interferons

Author

Jean-Philippe Herbeuval, Annette Martin, Nikaïa Smith, Marlène Dreux, Ségolène Gracias, Laura Sinigaglia, Nolwenn Jouvenet, Elodie Décembre, Matthieu Fritz, Frédéric Tangy, Daniela Bruni, Génomique virale et vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, 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), Génétique moléculaire des virus à ARN, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), We thank the following funding agencies: Agence Nationale pour la Recherche (ANR-12-JSV3-003-01, ANR-16-CE15-0025-01), Ville de Paris EMERGENCES Program, Marie Curie International Reintegration program PCIG11-GA-2012-322060, Centre National de la Recherche Scientifique (CNRS), Institut Pasteur and the EMBO YIP program. L.S. was supported by the Pasteur Paris University (PPU) International PhD program through an ‘Institut Carnot Pasteur Maladies Infectieuses’ grant. M.F. was the recipient of a Université Paris Diderot PhD fellowship, ANR-12-JSV3-0003,Viropero,Modulation spatiale et temporelle de la réponse antivirale MAVS(2012), ANR-16-CE15-0025,Viro-Storm,Mécanismes de production incontrôlée de cytokines au cours de l'infection virale(2016), European Project: 322060,EC:FP7:PEOPLE,FP7-PEOPLE-2012-CIG,VIROPERO(2012), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), ANR-16-CE15-0025,Viro-Storm,Mécanismes de production incontrôlée de cytokines au cours de l’infection virale(2016), 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), jouvenet, nolwenn, Jeunes Chercheuses et Jeunes Chercheurs - Modulation spatiale et temporelle de la réponse antivirale MAVS - - Viropero2012 - ANR-12-JSV3-0003 - JC - VALID, Mécanismes de production incontrôlée de cytokines au cours de l'infection virale - - Viro-Storm2016 - ANR-16-CE15-0025 - AAPG2016 - VALID, and TEMPORAL AND SPATIAL MODULATION OF ANTIVIRAL MAVS SIGNALING - VIROPERO - - EC:FP7:PEOPLE2012-08-01 - 2016-07-31 - 322060 - VALID

Subjects
0301 basic medicine, Adult, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Hepatitis C virus, viruses, lcsh:Medicine, Dengue virus, medicine.disease_cause, Virus, Article, 03 medical and health sciences, Flaviviridae, Young Adult, Capsid, Yellow Fever, medicine, Humans, lcsh:Science, Cells, Cultured, Aged, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Multidisciplinary, biology, lcsh:R, Virion, RNA, hemic and immune systems, TLR7, Dendritic Cells, Middle Aged, biology.organism_classification, Virology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Flavivirus, 030104 developmental biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, RNA, Viral, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Female, Interferons, Antibody, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Yellow fever virus
Abstract

Plasmacytoid dendritic cells (pDCs) are specialized in the production of interferons (IFNs) in response to viral infections. The Flaviviridae family comprises enveloped RNA viruses such as Hepatitis C virus (HCV) and Dengue virus (DENV). Cell-free flaviviridae virions poorly stimulate pDCs to produce IFN. By contrast, cells infected with HCV and DENV potently stimulate pDCs via short-range delivery of viral RNAs, which are either packaged within immature virions or secreted exosomes. We report that cells infected with Yellow fever virus (YFV), the prototypical flavivirus, stimulated pDCs to produce IFNs in a TLR7- and cell contact- dependent manner. Such stimulation was unaffected by the presence of YFV neutralizing antibodies. As reported for DENV, cells producing immature YFV particles were more potent at stimulating pDCs than cells releasing mature virions. Additionally, cells replicating a release-deficient YFV mutant or a YFV subgenomic RNA lacking structural protein-coding sequences participated in pDC stimulation. Thus, viral RNAs produced by YFV-infected cells reach pDCs via at least two mechanisms: within immature particles and as capsid-free RNAs. Our work highlights the ability of pDCs to respond to a variety of viral RNA-laden carriers generated from infected cells.

Published
2018
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4. Antiviral Response by Plasmacytoid Dendritic Cells via Interferogenic Synapse with Infected Cells

Author

Brian Webster, Omran Allatif, Séverin Coléon, Sonia Assil, Elodie Décembre, Marlène Dreux, and Lee Sherry

Subjects
hemic and immune systems, Biology, medicine.disease, Endocytosis, Dengue fever, Cell biology, Synapse, Interferon, medicine, Secretion, Receptor, Actin, Function (biology), medicine.drug
Abstract

SummaryType I interferon (IFN-I) is critical for protection against viral infections. Plasmacytoid dendritic cells (pDCs) massively produce IFN-I against viruses. Physical contacts are required for pDC-mediated sensing of cells infected by genetically distant viruses. How and why these contacts are established remains enigmatic. Using dengue, hepatitis C, zika viruses, we demonstrate that the pDC/infected cell interface is a specialized platform for viral immunostimulatory-RNA transfer, which we named interferogenic synapse and required for pDC-mediated antiviral response. This synapse is an exquisitely differentiated territory with polarized adhesion complexes and regulators of actin network and endocytosis. Toll-like receptor 7-induced signaling in pDCs promotes the interferogenic synapse establishment, thus providing a feed-forward regulation that sustains contacts with infected cells. We propose that the interferogenic synapse is crucial to pDC function as it allows scanning of infected cells to locally secrete IFN-I at the infection site, thereby confining a response potentially deleterious to the host.HighlightspDCs adhere to infected cells via αLβ2 integrin/ICAM-1Regulators of actin network and endocytosis polarize at contactTLR7-induced signaling potentiates pDC polarityInfected cells activate pDCs by interferogenic synapse

Published
2018
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5. Author response: Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

Author

Matthew L. Albert, Isabelle Bouvier, Biljana Zafirova, Darragh Duffy, Pierre-Emmanuel Joubert, Scott W Werneke, Thierry Walzer, Elodie Décembre, Marlène Dreux, Séverin Coléon, Helena Paidassi, Sebastien This, and Brian Webster

Subjects
0301 basic medicine, Biology, medicine.disease, medicine.disease_cause, Virology, Virus, Dengue fever, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Interferon, medicine, IRF7, Chikungunya, 030215 immunology, medicine.drug
Published
2018
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6. Les exosomes

Author

Elodie Décembre, Sonia Assil, and Marlène Dreux

Subjects
0303 health sciences, biology, Hepacivirus, RNA, General Medicine, biology.organism_classification, Virology, General Biochemistry, Genetics and Molecular Biology, Microvesicles, 03 medical and health sciences, 0302 clinical medicine, Immunization, Viral immunology, 030217 neurology & neurosurgery, 030304 developmental biology
Published
2013
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7. Sensing of immature particles produced by dengue virus infected cells induces an antiviral response by plasmacytoid dendritic cells

Author

Andrew D. Davidson, Elodie Décembre, Sonia Assil, Gavin R. Screaton, Marlène Dreux, Juthathip Mongkolsapaya, Wanwisa Dejnirattisai, Marine L. B. Hillaire, Naiglin, Laurence, Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
lcsh:Immunologic diseases. Allergy, [SDV]Life Sciences [q-bio], viruses, Immunology, Dengue virus, medicine.disease_cause, Membrane Fusion, Microbiology, Virus, Cell Line, 03 medical and health sciences, Viral envelope, Viral Envelope Proteins, Virology, Emerging Viral Diseases, Genetics, medicine, Humans, Molecular Biology, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, Innate Immune System, Innate immune system, biology, 030306 microbiology, Immunity, virus diseases, Biology and Life Sciences, hemic and immune systems, TLR7, Dendritic Cells, Dengue Virus, biology.organism_classification, Actin cytoskeleton, Biological Evolution, Immunity, Innate, 3. Good health, [SDV] Life Sciences [q-bio], Flavivirus, Actin Cytoskeleton, lcsh:Biology (General), Immune System, Parasitology, Cytokine secretion, lcsh:RC581-607, Research Article
Abstract

Dengue virus (DENV) is the leading cause of mosquito-borne viral illness and death in humans. Like many viruses, DENV has evolved potent mechanisms that abolish the antiviral response within infected cells. Nevertheless, several in vivo studies have demonstrated a key role of the innate immune response in controlling DENV infection and disease progression. Here, we report that sensing of DENV infected cells by plasmacytoid dendritic cells (pDCs) triggers a robust TLR7-dependent production of IFNα, concomitant with additional antiviral responses, including inflammatory cytokine secretion and pDC maturation. We demonstrate that unlike the efficient cell-free transmission of viral infectivity, pDC activation depends on cell-to-cell contact, a feature observed for various cell types and primary cells infected by DENV, as well as West Nile virus, another member of the Flavivirus genus. We show that the sensing of DENV infected cells by pDCs requires viral envelope protein-dependent secretion and transmission of viral RNA. Consistently with the cell-to-cell sensing-dependent pDC activation, we found that DENV structural components are clustered at the interface between pDCs and infected cells. The actin cytoskeleton is pivotal for both this clustering at the contacts and pDC activation, suggesting that this structural network likely contributes to the transmission of viral components to the pDCs. Due to an evolutionarily conserved suboptimal cleavage of the precursor membrane protein (prM), DENV infected cells release uncleaved prM containing-immature particles, which are deficient for membrane fusion function. We demonstrate that cells releasing immature particles trigger pDC IFN response more potently than cells producing fusion-competent mature virus. Altogether, our results imply that immature particles, as a carrier to endolysosome-localized TLR7 sensor, may contribute to regulate the progression of dengue disease by eliciting a strong innate response., Author Summary Viral recognition by the host often triggers an antiviral state, which suppresses viral spread and imparts adaptive immunity. Like many viruses, dengue virus (DENV) defeats the host-sensing pathway within infected cells. However, in vivo studies have demonstrated a key role of innate immunity in controlling DENV infection. Here we report that sensing of DENV-infected cells by non-permissive innate immune cells, the plasmacytoid dendritic cells (pDCs), triggers a cell-contact- and TLR7-dependent activation of a strong antiviral IFN response. This cell-to-cell sensing involves transmission of viral elements that are clustered at the interface between pDCs and infected cells and is regulated by the actin network. Importantly, we revealed that uncleaved prM surface protein-containing immature particles play a key function in stimulating the innate immune response. These non-infectious immature particles are released by infected cells as a consequence of a suboptimal cleavage site, which is an evolutionarily conserved viral feature that likely favors the export of infectious virus by prevention of premature membrane fusion in the secretory pathway. Therefore our results highlight a conceptually novel trade-off between efficient infectious virus release and the production of IFN-inducing particles. This concept may have broad importance for the many viruses that, like DENV, can disable the pathogen-sensing machinery within infected cells and can release uncleaved glycoprotein-containing non-infectious particles.

Published
2014

8. Short range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity

Author

Stefan Wieland, Francis V. Chisari, Marlène Dreux, Bryan Boyd, Urtzi Garaigorta, Elodie Décembre, Josan Chung, Christina Whitten-Bauer, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), 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), The Scripps Research Institute [La Jolla, San Diego], 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), The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Endosome, [SDV]Life Sciences [q-bio], Hepacivirus, Biology, Exosomes, Microbiology, Exosome, ESCRT, Article, 03 medical and health sciences, 0302 clinical medicine, Interferon, Immunology and Microbiology(all), Virology, medicine, Humans, Molecular Biology, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Innate immune system, RNA, TLR7, Dendritic Cells, Microvesicles, Immunity, Innate, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Hepatocytes, RNA, Viral, Parasitology, medicine.drug
Abstract

SummaryViral nucleic acids often trigger an innate immune response in infected cells. Many viruses, including hepatitis C virus (HCV), have evolved mechanisms to evade intracellular recognition. Nevertheless, HCV-permissive cells can trigger a viral RNA-, TLR7-, and cell-contact-dependent compensatory interferon response in nonpermissive plasmacytoid dendritic cells (pDCs). Here we report that these events are mediated by transfer of HCV-RNA-containing exosomes from infected cells to pDCs. The exosomal viral RNA transfer is dependent on the endosomal sorting complex required for transport (ESCRT) machinery and on Annexin A2, an RNA-binding protein involved in membrane vesicle trafficking, and is suppressed by exosome release inhibitors. Further, purified concentrated HCV-RNA-containing exosomes are sufficient to activate pDCs. Thus, vesicular sequestration and exosomal export of viral RNA may serve both as a viral strategy to evade pathogen sensing within infected cells and as a host strategy to induce an unopposed innate response in replication-nonpermissive bystander cells.

Published
2012
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9. ERK1 Regulates the Hematopoietic Stem Cell Niches

Author

Françoise Porteu, Elodie Décembre, Vincent Feuillet, Soizic Guihard, Jacques Pouysségur, Pierre Jurdic, Gilles Pagès, Nathalie Saulnier, Xavier Holy, Denis Clay, Murielle Gaudry, Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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 Biomédicale des Armées (IRBA), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-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), Université de Nice Sophia-Antipolis (UNSA), Agence Nationale pour la Recherche [ANR-08-BLAN-0332], Ministere de l'Enseignement Superieur et de la Recherche, Institut National de la sante et de la recherche medicale (INSERM), Association pour la Recherche contre le Cancer [SFI20101201698], Ligue Contre le Cancer, comite d'Ile de France [RS11/75-24], Institut National du Cancer (CSHLE) [2008 INCa], ProdInra, Migration, Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon)

Subjects
Myeloid, Cellular differentiation, [SDV]Life Sciences [q-bio], lcsh:Medicine, Monocytes, ACTIVATION, Mice, 0302 clinical medicine, Bone Density, Bone Marrow, Cell Movement, Osteogenesis, Bone cell, Molecular Cell Biology, Stem Cell Niche, lcsh:Science, 0303 health sciences, Multidisciplinary, Mitogen-Activated Protein Kinase 3, Stem Cells, OSTEOCLASTS, Hematopoietic stem cell, Cell Differentiation, Animal Models, COLONY-STIMULATING FACTOR, Signaling Cascades, Cell biology, [SDV] Life Sciences [q-bio], Haematopoiesis, medicine.anatomical_structure, DIFFERENTIATION, Cellular Microenvironment, MYELOLINEAGE COMMITMENT, PROTEIN-KINASE PATHWAY, MAP KINASE, KNOCKOUT MICE, BONE, RECEPTOR, Research Article, Signal Transduction, Biology, [INFO] Computer Science [cs], Bone and Bones, 03 medical and health sciences, Model Organisms, medicine, Animals, Cell Lineage, [INFO]Computer Science [cs], Progenitor cell, 030304 developmental biology, Cell Proliferation, Osteoblasts, Macrophages, lcsh:R, Molecular Development, Hematopoietic Stem Cells, Cell Compartmentation, Mice, Inbred C57BL, lcsh:Q, Bone marrow, 030217 neurology & neurosurgery, Gene Deletion, Homing (hematopoietic), Developmental Biology
Abstract

International audience; The mitogen-activated protein kinases (MAPK) ERK1 and ERK2 are among the major signal transduction molecules but little is known about their specific functions in vivo. ERK activity is provided by two isoforms, ERK1 and ERK2, which are ubiquitously expressed and share activators and substrates. However, there are not in vivo studies which have reported a role for ERK1 or ERK2 in HSCs and the bone marrow microenvironment. The present study shows that the ERK1-deficient mice present a mild osteopetrosis phenotype. The lodging and the homing abilities of the ERK1(-/-) HSC are impaired, suggesting that the ERK1(-/-)-defective environment may affect the engrafment of HSCs. Serial transplantations demonstrate that ERK1 is involved in the maintenance of an appropriate medullar microenvironment, but that the intrinsic properties of HSCs are not altered by the ERK1(-/-) defective microenvironment. Deletion of ERK1 impaired in vitro and in vivo osteoclastogenesis while osteoblasts were unaffected. As osteoclasts derive from precursors of the monocyte/macrophage lineage, investigation of the monocytic compartment was performed. In vivo analysis of the myeloid lineage progenitors revealed that the frequency of CMPs increased by approximately 1.3-fold, while the frequency of GMPs significantly decreased by almost 2-fold, compared with the respective WT compartments. The overall mononuclear-phagocyte lineage development was compromised in these mice due to a reduced expression of the M-CSF receptor on myeloid progenitors. These results show that the cellular targets of ERK1 are M-CSFR-responsive cells, upstream to osteoclasts. While ERK1 is well known to be activated by M-CSF, the present results are the first to point out an ERK1-dependent M-CSFR regulation on hematopoietic progenitors. This study reinforces the hypothesis of an active cross-talk between HSCs, their progeny and bone cells in the maintenance of the homeostasis of these compartments.

Published
2012
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