1. Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses
- Author
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Brian Webster, Scott W Werneke, Biljana Zafirova, Sébastien This, Séverin Coléon, Elodie Décembre, Helena Paidassi, Isabelle Bouvier, Pierre-Emmanuel Joubert, Darragh Duffy, Thierry Walzer, Matthew L Albert, Marlène Dreux, Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, 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), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, This work was supported by grants from the ‘Agence Nationale pour la Recherche’ (ANR-JCJC-EXAMIN), the ‘‘Agence Nationale pour la Recherche contre le SIDA et les Hépatites Virales’’ (ANRS-AO 2016–01) and the LabEx Ecofect Grant ANR-11-LABX-0048 to MD, ANR-14-CE14-0015-02 CHIKV-Viro-Immuno to MLA. BW’s postdoctoral fellowship was sponsored by EMBO (ALTF 1466–2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, We thank A Davidson (Bristol University) for providing the DENV-2 strain New Guinea C, P Despres (Pasteur Institut, Paris, France) for the anti-E DENV 3H5 antibody, V Lotteau (CIRI, Lyon, France) for Influenza A virus stocks, FV Chisari (Scripps Research Institute, La Jolla, CA) for the Huh-7.5.1 cells, T Taniguchi (University of Tokyo, Tokyo, Japan) for the Irf3/7 DKO mice, J Tschopp for the cardif-/- mice, and S Akira for the Tlr7-/- mice. We are grateful to Y Jaillais for critical reading of the manuscript, F Fusil for assistance with mice and to our colleagues for encouragement and help. We acknowledge the contribution of SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) facilities, PBES and cytometry for mice housing and technical assistance., ANR-13-JSV3-0004,EXAMIN,Les Exosomes enrichis en ARN viraux sont Médiateurs de la réponse Interféron(2013), ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), 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), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vougny, Marie-Christine, Jeunes Chercheuses et Jeunes Chercheurs - Les Exosomes enrichis en ARN viraux sont Médiateurs de la réponse Interféron - - EXAMIN2013 - ANR-13-JSV3-0004 - JC - VALID, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, and Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID
- Subjects
Male ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,QH301-705.5 ,Science ,Interferon Regulatory Factor-7 ,viruses ,Dengue ,immunology ,Interferon-gamma ,Mice ,Animals ,Humans ,dendritic cells ,human ,Biology (General) ,mouse ,Mice, Knockout ,virus diseases ,hemic and immune systems ,Dengue Virus ,Survival Analysis ,virology ,Killer Cells, Natural ,Mice, Inbred C57BL ,interferons ,Disease Models, Animal ,Gene Expression Regulation ,inflammation ,Host-Pathogen Interactions ,Interferon Type I ,Medicine ,Chikungunya Fever ,RNA, Viral ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Interferon Regulatory Factor-3 ,Chikungunya virus ,Spleen ,Signal Transduction - Abstract
International audience; Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.
- Published
- 2018