1. Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity
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Nikaïa Smith, Céline Possémé, Vincent Bondet, Jamie Sugrue, Liam Townsend, Bruno Charbit, Vincent Rouilly, Violaine Saint-André, Tom Dott, Andre Rodriguez Pozo, Nader Yatim, Olivier Schwartz, Minerva Cervantes-Gonzalez, Jade Ghosn, Paul Bastard, Jean Laurent Casanova, Tali-Anne Szwebel, Benjamin Terrier, Niall Conlon, Cliona O’Farrelly, Clíona Ní Cheallaigh, Nollaig M. Bourke, Darragh Duffy, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Trinity College Dublin, Saint James Hospital (SJH), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Datactix, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, CHU Necker - Enfants Malades [AP-HP], Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Howard Hughes Medical Institute (HHMI), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This study was supported by the 'URGENCE COVID-19' fundraising campaign of the Institut Pasteur (CoVarImm and Steroid Response), from the Agence Nationale de la Recherche (ANR-flash COVID-19), by the Laboratoire d’Excellence ‘Milieu Intérieur’ (grant no. ANR-10-LABX-69-01) (D.D.), the Fonds IMMUNOV for Innovation in Immunopathology (B.T.), and Science Foundation Ireland (C.O.F., C.N.C., and N.B.). We thank the STTAR-Bioresource of TCD-SJH-TUH COVID-19 bioresource which supported the collection of patient samples. N.S. is a recipient of the Pasteur–Roux–Cantarini Fellowship. C.O.F., N.C., and C.N.C. are part-funded by a Science Foundation Ireland (SFI) grant, Grant Code 20/SPP/3685. L.T. is supported by the Irish Clinical Academic Training (ICAT) Program, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland. N.B. is funded under the Science Foundation Ireland Phase 2 COVID-19 Rapid Response Call (20/COV/8487) and the Health Research Board COVID-19 Rapid Response Call (COV19e2020e053). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), ANR AABIFNCOV (ANR-20-CO11-0001) and ANR GenMISC (ANR-21-COVR-0039) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement No. 824110 (EASI-genomics), the Square Foundation, Grandir—Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM and the University of Paris (J.L.C.). P.B. was supported by the MD–Ph.D. program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller)., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Nanostring analysis. We thank Quanterix for the provision of IFNα multi-subtype prototype assays. We acknowledge all healthcare workers involved in the diagnosis and treatment of patients in Hopital Cochin, Hopital Bichat, and St James’s Hospital Dublin., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), and European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019)
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Proteomics ,Multidisciplinary ,SARS-CoV-2 ,[SDV]Life Sciences [q-bio] ,Interferon Type I ,General Physics and Astronomy ,Humans ,COVID-19 ,Interferon-alpha ,General Chemistry ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Autoantibodies - Abstract
Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies.
- Published
- 2022
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