RES EARCH ◥ may underlie critical COVID-19. We searched RESEARCH ARTICLE SUMMARY for auto-Abs against type I IFNs in 987 pa- tients hospitalized for life-threatening COVID- CORONAVIRUS 19 pneumonia, 663 asymptomatic or mildly affected individuals infected with SARS- Autoantibodies against type I IFNs in patients CoV-2, and 1227 healthy controls from whom samples were collected before the COVID- with life-threatening COVID-19 19 pandemic. Paul Bastard*† and Lindsey B. Rosen† et al. RESULTS: At least 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia INTRODUCTION: Interindividual clinical vari- kine immunity exist, in which neutralizing had neutralizing immunoglobulin G (IgG) ability is vast in humans infected with autoantibodies (auto-Abs) against interferon-g auto-Abs against IFN-w (13 patients), against severe acute respiratory syndrome corona- (IFN-g) (mycobacterial disease), interleukin-6 the 13 types of IFN-a (36), or against both (52) virus 2 (SARS-CoV-2), ranging from silent in- (IL-6) (staphylococcal disease), and IL-17A and at the onset of critical disease; a few also had fection to rapid death. Three risk factors for IL-17F (mucocutaneous candidiasis) mimic the auto-Abs against the other three individual life-threatening coronavirus disease 2019 clinical phenotypes of germline mutations of type I IFNs. These auto-Abs neutralize high (COVID-19) pneumonia have been identified— the genes that encode the corresponding cyto- concentrations of the corresponding type I being male, being elderly, or having other kines or receptors. Human inborn errors of IFNs, including their ability to block SARS- medical conditions—but these risk factors type I IFNs underlie severe viral respiratory CoV-2 infection in vitro. Moreover, all of the cannot explain why critical disease remains diseases. Neutralizing auto-Abs against type I patients tested had low or undetectable serum relatively rare in any given epidemiological IFNs, which have been found in patients with IFN-a levels during acute disease. These auto- group. Given the rising toll of the COVID-19 a few underlying noninfectious conditions, Abs were present before infection in the pandemic in terms of morbidity and mortality, have not been unequivocally shown to un- patients tested and were absent from 663 understanding the causes and mechanisms of derlie severe viral infections. While search- individuals with asymptomatic or mild SARS- life-threatening COVID-19 is crucial. ing for inborn errors of type I IFN immunity CoV-2 infection (P < 10−16). They were present in patients with life-threatening COVID-19 in only 4 of 1227 (0.33%) healthy individuals RATIONALE: B cell autoimmune infectious pneumonia, we also tested the hypothesis (P < 10−16) before the pandemic. The patients phenocopies of three inborn errors of cyto- that neutralizing auto-Abs against type I IFNs with auto-Abs were 25 to 87 years old (half were over 65) and of various ancestries. No- SARS-COV-2 tably, 95 of the 101 patients with auto-Abs Downloaded from https://www.science.org on February 24, 2022 were men (94%). Asymptomatic/mild Life-threatening CONCLUSION: A B cell autoimmune phenocopy of inborn errors of type I IFN immunity ac- counts for life-threatening COVID-19 pneumo- nia in at least 2.6% of women and 12.5% of men. In these patients, adaptive autoimmunity im- pairs innate and intrinsic antiviral immunity. These findings provide a first explanation for 0/663 (0%) 101/987 (10.2%) the excess of men among patients with life- threatening COVID-19 and the increase in Neutralizing auto-Abs impair type I IFN immunity risk with age. They also provide a means of Type I IFN immunity Auto-Abs to type I IFNs identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, includ- ing plasmapheresis, plasmablast depletion, IFNAR2 IFNAR2 IFNAR1 IFNAR1 and recombinant type I IFNs not targeted by TLR3 TLR3 the auto-Abs (e.g., IFN-b). ▪ The full author list and the list of author affiliations is pSTATs pSTATs available in the full article online. *Corresponding authors: Jean-Laurent Casanova (jean-laurent.casanova@rockefeller.edu); Paul Bastard ISGs ISGs (paul.bastard@institutimagine.org) IRF7 IRF7 †These authors contributed equally to this work. This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/), which Neutralizing auto-Abs to type I IFNs underlie life-threatening COVID-19 pneumonia. We tested the hypothesis permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19 by impairing the binding of type I Cite this article as P. Bastard et al., Science 370, eabd4585 IFNs to their receptor and the activation of the downstream responsive pathway. Neutralizing auto-Abs are (2020). DOI: 10.1126/science.abd4585 represented in red, and type I IFNs are represented in blue. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. ISGs, IFN-stimulated genes; TLR, Toll-like receptor; IFNAR, IFN-a/b receptor; READ THE FULL ARTICLE AT pSTAT, phosphorylated signal transducers and activators of transcription; IRF, interferon regulatory factor. https://doi.org/10.1126/science.abd4585 Bastard et al., Science 370, 423 (2020) 23 October 2020 1 of 1 RES EARCH ◥ patients with biallelic, hypomorphic RAG1 or RESEARCH ARTICLE RAG2 mutations and viral diseases including severe chickenpox and viral pneumonias (21). CORONAVIRUS Our attention was drawn to three patients with APS-1, with known preexisting anti–type I IFN Autoantibodies against type I IFNs in patients with auto-Abs, who had life-threatening coronavirus disease 2019 (COVID-19) pneumonia (22) (see life-threatening COVID-19 detailed case reports in Methods). While search- ing for inborn errors of type I IFNs (18, 23), we Paul Bastard1,2,3*†, Lindsey B. Rosen4†, Qian Zhang3‡, Eleftherios Michailidis5‡, Hans-Heinrich Hoffmann5‡, hypothesized that neutralizing auto-Abs against Yu Zhang4‡, Karim Dorgham6‡, Quentin Philippot1,2‡, Jérémie Rosain1,2‡, Vivien Béziat1,2,3‡, type I IFNs might also underlie life-threatening Jérémy Manry1,2, Elana Shaw4, Liis Haljasmägi7, Pärt Peterson7, Lazaro Lorenzo1,2, Lucy Bizien1,2, COVID-19 pneumonia. Sophie Trouillet-Assant8,9, Kerry Dobbs4, Adriana Almeida de Jesus4, Alexandre Belot10,11,12, Anne Kallaste13, Emilie Catherinot14, Yacine Tandjaoui-Lambiotte15, Jeremie Le Pen5, Gaspard Kerner1,2, Benedetta Bigio3, Auto-Abs against IFN-a2 and/or IFN-w in Yoann Seeleuthner1,2, Rui Yang3, Alexandre Bolze16, András N. Spaan3,17, Ottavia M. Delmonte4, patients with critical COVID-19 Michael S. Abers4, Alessandro Aiuti18, Giorgio Casari18, Vito Lampasona18, Lorenzo Piemonti18, Fabio Ciceri18, We searched for auto-Abs against type I IFNs in Kaya Bilguvar19, Richard P. Lifton19,20,21, Marc Vasse22, David M. Smadja23, Mélanie Migaud1,2, 987 patients hospitalized for life-threatening Jérome Hadjadj24, Benjamin Terrier25, Darragh Duffy26, Lluis Quintana-Murci27,28, Diederik van de Beek29, COVID-19 pneumonia. We also examined 663 Lucie Roussel30,31, Donald C. Vinh30,31, Stuart G. Tangye32,33, Filomeen Haerynck34, David Dalmau35, individuals infected with severe acute respira- Javier Martinez-Picado36,37,38, Petter Brodin39,40, Michel C. Nussenzweig41,42, Stéphanie Boisson-Dupuis1,2,3, tory syndrome coronavirus 2 (SARS-CoV-2) Carlos Rodríguez-Gallego43,44, Guillaume Vogt45, Trine H. Mogensen46,47, Andrew J. Oler48, Jingwen Gu48, presenting asymptomatic infection or mild Peter D. Burbelo49, Jeffrey I. Cohen50, Andrea Biondi51, Laura Rachele Bettini51, Mariella D'Angio51, disease and 1227 healthy controls whose Paolo Bonfanti52, Patrick Rossignol53, Julien Mayaux54, Frédéric Rieux-Laucat24, Eystein S. Husebye55,56,57, samples were collected before the COVID-19 Francesca Fusco58, Matilde Valeria Ursini58, Luisa Imberti59, Alessandra Sottini59, Simone Paghera59, pandemic. Plasma or serum samples were Eugenia Quiros-Roldan60, Camillo Rossi61, Riccardo Castagnoli62, Daniela Montagna63,64, collected from patients with critical COVID- Amelia Licari62, Gian Luigi Marseglia62, Xavier Duval65,66,67,68,69, Jade Ghosn68,69, HGID Lab§, 19 during the acute phase of disease. Multiplex NIAID-USUHS Immune Response to COVID Group§, COVID Clinicians§, COVID-STORM Clinicians§, particle-based flow cytometry revealed a high Imagine COVID Group§, French COVID Cohort Study Group§, The Milieu Intérieur Consortium§, fluorescence intensity (FI) (>1500) for IgG CoV-Contact Cohort§, Amsterdam UMC Covid-19 Biobank§, COVID Human Genetic Effort§, auto-Abs against IFN-a2 and/or IFN-w in 135 John S. Tsang70,71, Raphaela Goldbach-Mansky4, Kai Kisand7, Michail S. Lionakis4, Anne Puel1,2,3, patients (13.7%) with life-threatening COVID-19 Shen-Ying Zhang1,2,3, Steven M. Holland4¶, Guy Gorochov6,72¶, Emmanuelle Jouanguy1,2,3¶, (Fig. 1A). We found that 49 of these 135 pa- Downloaded from https://www.science.org on February 24, 2022 Charles M. Rice5¶, Aurélie Cobat1,2,3¶, Luigi D. Notarangelo4¶, Laurent Abel1,2,3¶, tients were positive for auto-Abs against both Helen C. Su4#, Jean-Laurent Casanova1,2,3,42,73*# IFN-a2 and IFN-w, whereas 45 were positive only for auto-Abs against IFN-a2, and 41 were Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 positive only for auto-Abs against IFN-w. (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening We also performed enzyme-linked immuno- coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies sorbent assay (ELISA), and the results ob- (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both tained were consistent with those obtained (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The with Luminex technology (fig. S1A). We found auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These that 11 and 14 of 23 patients tested had low auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were levels of IgM and IgA auto-Abs against IFN-w present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of and IFN-a2, respectively (Fig. 1B and fig. S1B). the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life- Auto-Abs against type I IFNs were detected in threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men. two unrelated patients for whom we had plas- ma samples obtained before SARS-CoV-2 in- M fection, which indicates that these antibodies ycobacteriosis, staphylococcosis, and trimers (STAT, signal transducers and activa- were present before SARS-CoV-2 infection and candidiasis can be driven by mono- tors of transcription; IRF, interferon regula- were not triggered by the infection. As a con- genic inborn errors of interferon-g tory factor) (14). Neutralizing immunoglobulin trol, we confirmed that all 25 APS-1 patients (IFN-g), interleukin-6 (IL-6), and IL- G (IgG) auto-Abs against type I IFNs can occur tested had high levels of auto-Abs against IFN- 17A and IL-17F, respectively, or they in patients treated with IFN-a2 or IFN-b (15) a2 and IFN-w (fig. S1C). Overall, we found that can be driven by their genetically driven auto- and exist in almost all patients with auto- 135 of 987 patients (13.7%) with life-threatening immune phenocopies, with the production of immune polyendocrinopathy syndrome type I COVID-19 pneumonia had IgG auto-Abs against neutralizing autoantibodies (auto-Abs) against (APS-1) (16). They are also seen in women with at least one type I IFN. these cytokines (1–8). Type I IFNs, first de- systemic lupus erythematosus (17). scribed in 1957, are ubiquitously expressed These patients do not seem to suffer from The auto-Abs neutralize IFN-a2 and IFN-w in vitro cytokines that contribute to both innate im- unusually severe viral infections, although hu- We then tested whether auto-Abs against IFN- munity (through their secretion by plasma- man inborn errors of type I IFNs can underlie a2 and IFN-w were neutralizing in vitro. We cytoid dendritic cells and other leukocytes) severe viral diseases, both respiratory and incubated peripheral blood mononuclear cells and cell-intrinsic immunity (in most if not all otherwise (18). In 1984, Ion Gresser described (PBMCs) from healthy controls with 10 ng/mL cell types) against viral infections (9–13). Their a patient with unexplained auto-Abs against IFN-a2 or IFN-w in the presence of plasma receptors are ubiquitously expressed and trig- type I IFNs suffering from severe chickenpox from healthy individuals or from patients ger the induction of IFN-stimulated genes and shingles (19, 20). More recently, auto-Abs with auto-Abs. A complete abolition of STAT1 (ISGs) via phosphorylated STAT1-STAT2-IRF9 against type I IFNs have been found in a few phosphorylation was observed in 101 patients Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 1 of 12 RES EARCH | R E S E A R C H A R T I C L E with auto-Abs against IFN-a2 and/or IFN-w the presence of plasma from healthy individ- type I IFNs. ELISA showed that all patients (table S1). The antibodies detected were neu- uals or from patients with auto-Abs. With plas- tested (N = 22) with auto-Abs against IFN-a2 tralizing against both IFN-a2 and IFN-w in 52 ma from eight patients with auto-Abs against also had auto-Abs against all 13 IFN-a sub- of these 101 patients (51%), against only IFN- IFN-a2, the induction of ISG CXCL10 was abo- types (IFN-a1, -a2, -a4, -a5, -a6, -a7, -a8, -a10, a2 in 36 patients (36%), and against only IFN- lished after IFN-a2 stimulation but maintained -a13, -a14, -a16, -a17, and -a21), whereas only 2 w in 13 patients (13%) at the IFN-a2 and IFN-w after stimulation with IFN-g (Fig. 1F). We then of the 22 patients tested had auto-Abs against concentrations tested (Fig. 1, C and D). IgG found that plasma from the five patients with IFN-b, 1 had auto-Abs against IFN-k, and 2 depletion from patients with auto-Abs restored neutralizing auto-Abs neutralized the protec- had auto-Abs against IFN-e (Fig. 2A). The normal pSTAT1 induction after IFN-a2 and tive activity of IFN-a2 in Madin–Darby bovine auto-Abs against IFN-b had neutralizing activ- IFN-w stimulation, whereas the purified IgG kidney (MDBK) cells infected with vesicular ity against IFN-b (Fig. 1D). We confirmed that fully neutralized this induction (Fig. 1C and stomatitis virus (VSV) (table S2). Overall, we all of the patients had auto-Abs against all 13 fig. S1D). Furthermore, these auto-Abs neutral- found that 101 of 987 patients (10.2%)—including subtypes of IFN-a by testing the same samples ized high amounts of IFN-a2 (fig. S1E) and 95 men (94%)—with life-threatening COVID-19 using luciferase-based immunoprecipitation as- were neutralizing at high dilutions (Fig. 1E pneumonia had neutralizing IgG auto-Abs say (LIPS) (Fig. 2B). For IFN-b, we also screened and fig. S1F). Notably, 15 patients with life- against at least one type I IFN. By contrast, the whole cohort in a multiplex assay. We threatening COVID-19 and auto-Abs against auto-Abs were detected in only 4 of 1227 healthy found that 19 of 987 (1.9%) patients had auto- IFN-a2 and/or IFN-w also had auto-Abs against controls (0.33%) (Fisher exact test, P < 10−16) Abs against IFN-b and that all of them were in other cytokines [IFN-g, granulocyte-macrophage and in none of the 663 patients with asymp- our cohort of severe COVID-19 individuals colony-stimulating factor (GM-CSF), IL-6, IL-10, tomatic or mild SARS-CoV-2 infection tested with neutralizing auto-Abs against IFN-a and/ IL-12p70, IL-22, IL-17A, IL-17F, and/or tumor (Fisher exact test, P < 10−16). or IFN-w. Of these patients with auto-Abs necrosis factor–b (TNFb)], only three of which against IFN-b, only two were neutralizing (IL-12p70, IL-22, and IL-6) were neutralizing Auto-Abs against all 13 IFN-a subtypes in against IFN-b (Fig. 1, D and F). (in four patients) (fig. S2, A to C). Similar patients with auto-Abs to IFN-a2 Ten of the 17 genes encoding type I IFNs proportions were observed in the other co- We investigated whether patients with neu- (IFN-a2, -a5, -a6, a8, -a13, -a14, -a21, -b, -w, and horts (fig. S2, D to L). tralizing auto-Abs against IFN-a2 only or those -k), have undergone strong negative selection, We also analyzed ISG induction after 2 hours with neutralizing auto-Abs against IFN-a2 and which suggests that they play an essential role of stimulation with IFN-a2, IFN-b, or IFN-g in IFN-w also had auto-Abs against the other 15 in the general population. By contrast, the 1 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. 2University of Paris, Imagine Institute, Paris, France. 3 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 4Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. 5Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. 6Sorbonne Université, INSERM, Centre d’Immunologie et des Maladies Infectieuses, (CIMI-Paris), Paris, France. 7Institute of Biomedicine and Translational Downloaded from https://www.science.org on February 24, 2022 Medicine, University of Tartu, Tartu, Estonia. 8Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France. 9International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France. 10International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France. 11National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children (RAISE), Lyon, France. 12Lyon Immunopathology Federation (LIFE), Hospices Civils de Lyon, Lyon, France. 13Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia. 14Pneumology Department, Foch Hospital, Suresne, France. 15Avicenne Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Bobigny, INSERM U1272 Hypoxia and Lung, Bobigny, France. 16Helix, San Mateo, CA, USA. 17Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands. 18IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy. 19Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. 20Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT, USA. 21Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA. 22Service de Biologie Clinique and UMR-S 1176, Hôpital Foch, Suresnes, France. 23INSERM UMR-S 1140, Biosurgical Research Laboratory (Carpentier Foundation), Paris University and European Georges Pompidou Hospital, Paris, France. 24Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, University of Paris, Imagine Institute, Paris, France. 25Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), University of Paris, Paris, France. 26Translational Immunology Laboratory, Institut Pasteur, Paris, France. 27 Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015, Paris, France. 28Human Genomics and Evolution, Collège de France, Paris, France. 29Amsterdam UMC, University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands. 30Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada. 31Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada. 32Garvan Institute of Medical Research, Darlinghurst 2010, NSW, Sydney, Australia. 33St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst 2010, NSW, Australia. 34Department of Paediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Laboratory, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium. 35 Infectious Diseases and HIV Service, Hospital Universitari Mutua Terrassa, Universitat de Barcelona, Fundació Docència i Recerca Mutua Terrassa, Terrassa, Barcelona, Catalonia, Spain. 36IrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain. 37Infectious Diseases and Immunity, Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain. 38Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. 39Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Karolinska, Sweden. 40Department of Pediatric Rheumatology, Karolinska University Hospital, Karolinska, Sweden. 41Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA. 42Howard Hughes Medical Institute, New York, NY, USA. 43Department of Immunology, Hospital Universitario de Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain. 44Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain. 45Neglected Human Genetics Laboratory, INSERM, University of Paris, Paris, France. 46Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark. 47Department of Biomedicine, Aarhus University, Aarhus, Denmark. 48Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA. 49Division of Intramural Research, National Institute of Dental Craniofacial Research (NIDCR), NIH, Bethesda, MD, USA. 50Laboratory of Infectious Diseases, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA. 51Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM- Ospedale, San Gerardo, Monza, Italy. 52Department of Infectious Diseases, San Gerardo Hospital - University of Milano-Bicocca, Monza, Italy. 53University of Lorraine, Plurithematic Clinical Investigation Centre INSERM CIC-P 1433, INSERM U1116, CHRU Nancy Hopitaux de Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France. 54Intensive Care Unit, Pitié- Salpétrière Hospital, Paris University, AP-HP, Paris, France. 55Department of Clinical Science and K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway. 56Department of Medicine, Haukeland University Hospital, Bergen, Norway. 57Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden. 58Human Molecular Genetics Laboratory, Institute of Genetics and Biophysics, “A. Buzzati-Traverso” Consiglio Nazionale delle Ricerche, Naples, Italy. 59Centro di Ricerca Emato-oncologica AIL (CREA) Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy. 60Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy. 61Direzione Sanitaria, ASST Spedali Civili di Brescia, Brescia, Italy. 62Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy. 63Laboratory of Immunology and Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 64Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy. 65INSERM CIC 1425, Paris, France. 66AP-HP, University Hospital of Bichat, Paris, France. 67University Paris Diderot, Paris 7, UFR de Médecine-Bichat, Paris, France. 68Infection, Antimicrobials, Modelling, Evolution (IAME), INSERM, UMRS1137, University of Paris, Paris, France. 69AP-HP, Bichat Claude Bernard Hospital, Infectious and Tropical Diseases Department, Paris, France. 70Center for Human Immunology, NIH, Bethesda, MD, USA. 71Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. 72Département d’Immunologie, AP-HP, Hôpital Pitié-Salpétrière, Paris, France. 73Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France. *Corresponding author. Email: jean-laurent.casanova@rockefeller.edu (J.-L.C.); paul.bastard@institutimagine.org (P.B.) †These authors contributed equally to this work. ‡These authors contributed equally to this work. §All collaborators and their affiliations appear at the end of this paper. ¶These authors contributed equally to this work. #These authors contributed equally to this work. Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 2 of 12 RES EARCH | R E S E A R C H A R T I C L E Downloaded from https://www.science.org on February 24, 2022 Fig. 1. Neutralizing auto-Abs against IFN-a2 and/or IFN-w in patients with neutralization capacity. The stimulation index (stimulated over unstimulated life-threatening COVID-19. (A) Multiplex particle-based assay for auto-Abs condition) for the plasma from each patient was normalized against that of healthy against IFN-a2 and IFN-w in patients with life-threatening COVID-19 (N = 782), in control plasma from the same experiment. Spearman’s rank correlation coefficient = patients with asymptomatic or mild SARS-CoV-2 infection (N = 443), and in −0.6805; P < 0.0001. (E) Median inhibitory concentration (IC50) curves healthy controls not infected with SARS-CoV-2 (N = 1160). (B) Anti–IFN-w Ig representing IFN-a2– and IFN-w–induced pSTAT1 levels in healthy donor cells isotypes in 23 patients with life-threatening COVID-19 and auto-Abs to type I in the presence of serial dilutions of patient plasma. The stimulation index IFNs. (C) Representative fluorescence-activated cell sorting (FACS) plots (stimulated over unstimulated condition) for patient plasma was normalized depicting IFN-a2– or IFN-w–induced pSTAT1 in healthy control cells (gated on against that of 10% healthy control plasma. IFN-a2: IC50 = 0.016%, R2 = 0.985; CD14+ monocytes) in the presence of 10% healthy control or anti–IFN-a2 or IFN-w: IC50 = 0.0353%, R2 = 0.926. R2, coefficient of determination. (F) Neutralizing anti–IFN-w auto-Abs–containing patient plasma (top panel) or an IgG-depleted effect on CXLC10 induction, after stimulation with IFN-a2, IFN-b, or IFN-g, in the plasma fraction (bottom panel). Max, maximum; neg, negative; pos, positive; presence of plasma from healthy controls (N = 4), patients with life-threatening NS, not stimulated. (D) Plot of anti–IFN-a2 auto-Ab levels against their COVID-19 and auto-Abs against IFN-a2 (N = 8), and APS-1 patients (N = 2). Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 3 of 12 RES EARCH | R E S E A R C H A R T I C L E Downloaded from https://www.science.org on February 24, 2022 Fig. 2. Auto-Abs against the different type I IFN subtypes. (A) ELISA for healthy controls (N = 2). (C) Neighbor-joining phylogenetic tree of the 17 human auto-Abs against the 13 different IFN-a subtypes, IFN-w, IFN-b, IFN-k, and IFN-e type I IFN proteins. Horizontal branches are drawn to scale (bottom left, number in patients with life-threatening COVID-19 and auto-Abs against IFN-a2 (N = 22), of substitutions per site). Thinner, intermediate, and thicker internal branches APS-1 patients (N = 2), and healthy controls (N = 2). (B) LIPS for the 12 different have bootstrap support of <50, ≥50, and >80%, respectively. The bootstrap IFN-a subtypes tested in patients with auto-Abs against IFN-a2 (N = 22) and value for the branch separating IFN-w from all IFN-a subtypes is 100%. other seven IFN loci in the human genome Huh7.5 cells with SARS-CoV-2 (Fig. 3A). Plas- izing auto-Abs against IFN-a is, therefore, often carry loss-of-function alleles (24). More- ma from two healthy controls or from seven strongly associated with low serum IFN-a levels over, the 13 IFN-a subtypes and IFN-w are SARS-CoV-2–infected patients without auto- (Fisher exact test, P < 10−6). Consistently in more-closely related to each other than they Abs did not block the protective action of IFN- patients with neutralizing auto-Abs against are to the other three IFNs (IFN-b, IFN-e, and a2 (Fig. 3A and fig. S3A). These data provide IFN-a2, the baseline levels of type I IFN– IFN-k), which are structurally and phyloge- compelling evidence that the patients’ blood dependent transcripts were low, whereas they netically more distant (Fig. 2C). Thus, all carried sufficiently large amounts of auto-Abs were normal for nuclear factor kB (NF-kB)– patients with neutralizing auto-Abs against to neutralize the corresponding type I IFNs and dependent transcripts (Fig. 3C and fig. S3B). IFN-a2 that we tested (N = 22) had auto-Abs block their antiviral activity in vitro, including Overall, our findings indicate that the auto- against all 13 IFN-a subtypes, and 3 of the 22 that against SARS-CoV-2. Abs against type I IFNs present in patients patients tested (14%) had auto-Abs against We also found that all 41 patients with neu- with life-threatening COVID-19 were neu- 14 or more type I IFNs. tralizing auto-Abs against the 13 types of IFN-a tralizing in vitro and in vivo. tested had low (one patient) or undetectable The auto-Abs neutralize IFN-a2 against (40 patients) levels of the 13 types of IFN-a in Pronounced excess of men in patients with SARS-CoV-2 in vitro and IFN-a in vivo their plasma during the course of the disease auto-Abs against type I IFNs Plasma from eight patients with neutralizing (Fig. 3B) (25, 26). Type I IFNs may be degraded There was a pronounced excess of male patients auto-Abs against type I IFN also neutralized and/or bound to the corresponding circulating (95 of 101; 94%) with critical COVID-19 pneu- the ability of IFN-a2 to block the infection of auto-Abs. The presence of circulating neutral- monia and neutralizing auto-Abs against type I Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 4 of 12 RES EARCH | R E S E A R C H A R T I C L E A B C Downloaded from https://www.science.org on February 24, 2022 Fig. 3. Enhanced SARS-CoV-2 replication, despite the presence of IFN-a2, (N = 41), healthy controls (N = 5), COVID-19 patients without auto-Abs (N = 21), and in the presence of plasma from patients with auto-Abs against IFN-a2 and patients with life-threatening COVID-19 and loss-of-function (LOF) variants (N = 10), low in vivo levels of IFN-a. (A) SARS-CoV-2 replication—measured 24 hours as assessed by Simoa ELISA. (C) z-scores for type I IFN gene responses in whole (left) and 48 hours (right) after infection—in Huh7.5 cells treated with IFN-a2 in the blood of COVID-19 patients with (N = 8) or without (N = 51) neutralizing auto-Abs, or presence of plasma from patients with life-threatening COVID-19 and neutralizing auto- healthy uninfected controls (N = 22). The median ± interquartile range is shown. Abs against IFN-a2 (N = 8); a commercial anti–IFN-a2 antibody; or control plasma z-scores were significantly lower for patients with neutralizing auto-Abs compared with (N = 2). (B) IFN-a levels in the plasma or serum of patients with neutralizing auto-Abs patients without auto-Abs (Mann-Whitney test, P = 0.01). threatening COVID-19 had X chromosome– Table 1. Sex and age distribution of patients with critical COVID-19 with and without auto-Abs. Ages linked incontinentia pigmenti (IP), in which and sexes of the patients and controls and information about auto-Abs against IFN-a2 and IFN-w, presented by cells activate only a single X chromosome (cells age and sex. Dashes in rightmost column indicate data not available. OR, odds ratio; CI, confidence interval. having activated the X chromosome bearing the null mutation in NEMO dying in the course Life-threatening N auto-Abs positive of development) (27). The prevalence of auto- N total OR [95% CI] P value* COVID-19 (percentage) Abs against type I IFNs in the general pop- ulation was estimated at 0.33% (0.015 to 0.67%) Sex ..................................................................................................................................................................................................................... in a sample of 1227 healthy individuals—a value Female 226 6 (2.6%) 1 – ..................................................................................................................................................................................................................... much lower than that in patients with life- Male 761 95 (12.5%) 5.22 [2.27 – 14.80] 2.5 × 10−6 ..................................................................................................................................................................................................................... threatening COVID-19 pneumonia, by a factor Age ..................................................................................................................................................................................................................... of at least 15. <65 years 602 51 (8.5%) 1 – ..................................................................................................................................................................................................................... The patients with auto-Abs were also slightly ≥65 years 385 50 (13.0%) 1.61 [1.04 – 2.49] 0.024 ..................................................................................................................................................................................................................... older than the rest of our cohort (49.5% of *P values were derived from Fisher’s exact test, as implemented in R (https://cran.r-project.org/). patients positive for auto-Abs were over 65 years of age versus 38% for the rest of the cohort; P = 0.024), which suggests that the frequency IFNs. This proportion of males was higher than or pauci-symptomatic cohort (28%; Fisher exact of circulating anti–type I IFNs auto-Abs in- that observed in patients with critical COVID-19 test, P < 10−6) (Table 1, Fig. 4A, and fig. S4A). creases with age (Table 1 and Fig. 4B). However, without auto-Abs (75%; Fisher exact test, P = Further evidence for X-chromosome linkage auto-Abs were found in patients aged from 2.5 × 10−6), and the proportion was much higher was provided by the observation that one 25 to 87 years (fig. S4B). Principal components than that in male patients in the asymptomatic of the seven women with auto-Abs and life- analysis (PCA) was performed on data from Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 5 of 12 RES EARCH | R E S E A R C H A R T I C L E Fig. 4. Demographic and ethnic information about the patients and and auto-Abs to type I IFNs, patients with life-threatening COVID-19 and controls. (A) Gender distribution in patients with life-threatening COVID-19 without auto-Abs to type I IFNs, and individuals with asymptomatic or mild and auto-Abs to type I IFNs, patients with life-threatening COVID-19 and SARS-CoV-2. yo, years old. (C) PCA on 49 patients with life-threatening without auto-Abs to type I IFNs, and individuals with asymptomatic or mild COVID-19 and auto-Abs against type I IFNs. EUR, Europeans; AFR, Africans; Downloaded from https://www.science.org on February 24, 2022 SARS-CoV-2. (B) Age distribution in patients with life-threatening COVID-19 EAS, East-Asians. 49 patients: 34 Europeans, 5 North Africans, driven by germ line or somatic genome—may with inborn errors of type I IFNs and life- 4 sub-Saharan Africans, 2 patients from the be X chromosome–linked and therefore pre- threatening COVID-19 (18), this study high- Middle East, 2 South Asians, 1 East Asian, existing to infection. lights the crucial role of type I IFNs in protective and 1 South American (Fig. 4C). Large-scale Moreover, IFN-a subtypes were undetect- immunity against SARS-CoV-2. These auto-Abs studies will be required to determine the fre- able during acute disease in the blood of against type I IFNs were clinically silent until quency of such auto-Abs in humans of differ- patients with auto-Abs against IFN-a, which the patients were infected with SARS-CoV-2— ent sexes, ages, and ancestries. Finally, the suggests a preexisting or concomitant biolog- a poor inducer of type I IFNs (28)—which sug- presence of auto-Abs was associated with a ical impact in vivo. It is also unlikely that gests that the small amounts of IFNs induced poor outcome, with death occurring in 37 of patients could break self-tolerance and mount by the virus are important for protection against the 101 patients (36.6%) (table S1). high titers of neutralizing IgG auto-Abs against severe disease. The neutralizing auto-Abs type I IFN within only 1 or even 2 weeks of against type I IFNs, like inborn errors of type I Neutralizing auto-Abs to type I IFNs are infection. Finally, inborn errors of type I IFNs IFN production, tip the balance in favor of the causative of critical COVID-19 underlying life-threatening COVID-19 in other virus, which results in devastating disease with There are multiple lines of evidence to suggest previously healthy adults—including autosomal insufficient, and even perhaps deleterious, in- that the neutralizing auto-Abs against type I recessive IFN-a/b receptor subunit 1 (IFNAR1) nate and adaptive immune responses. IFNs observed in these 101 patients preceded deficiency—have also been reported in an ac- Our findings have direct clinical implica- infection with SARS-CoV-2 and accounted for companying paper (18). Collectively, these find- tions. First, SARS-CoV-2–infected patients can the severity of disease. First, the two patients ings suggest that auto-Abs against type I IFNs be screened to identify individuals with auto- for whom testing was performed before COVID- are a cause and not a consequence of severe Abs at risk of developing life-threatening 19 were found to have auto-Abs before infec- SARS-Cov-2 infection, although their titers and pneumonia. Such patients recovering from tion. Second, three patients with APS-1 known affinity may be enhanced by the SARS-CoV-2– life-threatening COVID-19 should also be ex- to have neutralizing auto-Abs against type I driven induction of type I IFNs. They also pro- cluded from donating convalescent plasma for IFN immunity before infection also had life- vide an explanation for the major sex bias seen ongoing clinical trials, or at least they should threatening COVID-19 (22) (supplementary in patients with life-threatening COVID-19 and be tested before their plasma donations are methods). Third, we screened a series of 32 perhaps also for the increase in risk with age. accepted (29). Second, this finding paves the women with IP and found that a quarter of way for preventive or therapeutic intervention, them had auto-Abs against type I IFNs, in- Conclusion including plasmapheresis, monoclonal Abs de- cluding one who developed critical COVID-19 We report here that at least 10% of patients pleting plasmablasts, and the specific inhibi- (fig. S1C). Fourth, there is a marked bias in with life-threatening COVID-19 pneumonia tion of type I IFN–reactive B cells (30). Finally, in favor of men, which suggests that the produc- have neutralizing auto-Abs against type I IFNs. this patient group, early treatment with IFN-a tion of auto-Abs against type I IFNs—whether With our accompanying description of patients is unlikely to be beneficial; however, treatment Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 6 of 12 RES EARCH | R E S E A R C H A R T I C L E with injected or nebulized IFN-b may have (32). IFN-a1, IFN-a2, IFN-a4, IFN-a5, IFN-a6, (https://cran.r-project.org/). PCA was performed beneficial effects, as auto-Abs against IFN-b IFN-a7, IFN-a8, IFN-a10, IFN-a14, IFN-a16, with Plink v1.9 software on whole-exome and appear to be rare in patients with auto-Abs IFN-a17, and IFN-a21 sequences were trans- whole-genome sequencing data with the 1000 against type I IFNs. fected in HEK293 cells, and the IFN-a-luciferase Genomes (1kG) Project phase 3 public data- fusion proteins were collected in the tissue base as a reference. Materials and methods culture supernatant. For autoantibody screen- Subjects and samples ing, serum samples were incubated with Simoa We enrolled 987 patients with proven life- protein G agarose beads, and we then added Serum IFN-a concentrations were determined threatening (critical) COVID-19, 663 asympto- 2 × 106 luminescence units (LU) of antigen with Simoa technology, as previously described matic or pauci-symptomatic individuals with and incubated. Luminescence intensity was (40, 41), with reagents and procedures ob- proven COVID-19, and 1227 healthy controls measured. The results are expressed in arbi- tained from the Quanterix Corporation. in this study. All subjects were recruited fol- trary units (AU), as a fold-difference relative to lowing protocols approved by local Institutional the mean of the negative control samples. VSV assay Review Boards (IRBs). All protocols followed The seroneutralization assay was performed local ethics recommendations and informed Functional evaluation of anti-cytokine auto-Abs as previously described (42). In brief, the incu- consent was obtained when required. The blocking activity of anti–IFN-a and anti– bation of IFN-a2 with MDBK cells protects the COVID-19 disease severity was assessed in IFN-w auto-Abs was determined by assessing cultured cells against the cytopathic effect of accordance with the Diagnosis and Treatment STAT1 phosphorylation in healthy control cells VSV. The titer of anti–IFN-a antibodies was Protocol for Novel Coronavirus Pneumonia. after stimulation with the appropriate cyto- defined as the last dilution causing 50% cell The term life-threatening COVID-19 pneu- kines in the presence of 10% healthy control or death. monia describes pneumonia in patients with patient serum or plasma. critical disease, whether pulmonary, with We demonstrated that the IFN-a and IFN-w SARS-CoV-2 experiment mechanical ventilation [continuous positive blocking activity observed was due to auto-Abs SARS-CoV-2 strain USA-WA1/2020 was obtained airway pressure (CPAP), bilevel positive air- and not another plasma factor, by depleting from BEI Resources and amplified in Huh7.5 way pressure (BIPAP), intubation, or high-flow IgG from the plasma with a protein G column hepatoma cells at 33°C. Viral titers were mea- oxygen], septic shock, or damage to any other Without eluting the IgG, the flow-through sured on Huh7.5 cells in a standard plaque organ requiring admission in the intensive care fraction (IgG-depleted) was then collected and assay. Plasma samples or a commercial anti– unit (ICU). The individuals with asymptomatic compared with total plasma in the phospho- IFN-a2 antibody were serially diluted and or mild SARS-CoV-2 infection were individuals STAT1 assay. incubated with 20 pM recombinant IFN-a2 infected with SARS-CoV-2 who remained asy- The blocking activity of anti–IFN-g, –GM- for 1 hour at 37°C (starting concentrations: mptomatic or developed mild, self-healing, am- CSF, –IFN-l1, –IFN-l2, –IFN-l3, –IL-6, –IL-10, plasma samples = 1/100 and anti–IFN-a2 Downloaded from https://www.science.org on February 24, 2022 bulatory disease with no evidence of pneumonia. –IL-12p70, –IL-22, –IL-17A, –IL-17F, -TNFa, and antibody = 1/1000). The cell culture me- The healthy controls were individuals who -TNFb antibodies was assessed with the dium was then removed and replaced with had not been exposed to SARS-CoV-2. assays outlined in table S3, as previously the plasma– or antibody–IFN-a2 mixture. The Plasma and serum samples from the patients reported (21). plates were incubated overnight, and the and controls were frozen at −20°C immediately For the neutralization of ISG induction, plasma– or antibody–IFN-a2 mixture was after collection. The fluid-phase LIPS assay was PBMCs were left unstimulated or were stimu- removed by aspiration. The cells were washed used to determine the levels of antibodies against lated for 2 hours with 10 ng/mL IFN-a or 10 ng/ once with phosphate-buffered saline (PBS) to the SARS-CoV-2 nucleoprotein and spike pro- mL IFN-g in a final volume of 100 mL. Real- remove potential anti–SARS-CoV-2 neutral- tein, as has been previously described (31). time quantitative polymerase chain reaction izing antibodies, and fresh medium was then (RT-qPCR) analysis was performed with Ap- added. Cells were then infected with SARS- Detection of anti-cytokine auto-Abs plied Biosystems Taqman assays for CXCL10, CoV-2 by directly adding the virus to the wells. Multiplex particle-based assay and the b-glucuronidase (GUS) housekeeping Cells infected at a high multiplicity of infec- Serum and plasma samples were screened gene for normalization. Results are expressed tion (MOI) were incubated at 37°C for 24 hours, for auto-Abs against 18 targets in a multiplex according to the DDCt method, as described by whereas cells infected at a low MOI were particle-based assay, in which magnetic beads the manufacturer’s kit. incubated at 33°C for 48 hours. The cells with differential fluorescence were covalently were fixed with 7% formaldehyde, stained for coupled to recombinant human proteins. Patients Phylogenetic reconstruction SARS-CoV-2 with an anti-N antibody, imaged, with an FI of >1500 for IFN-a2 or IFN-b or Protein sequences were aligned with the online and analyzed as previously described (43). >1000 for IFN-w were tested for blocking activ- version of MAFFT v7.471 software (33), using ity, as were patients positive for another cytokine. the L-INS-i strategy (34) and the BLOSUM62 Nanostring scoring matrix for amino acid substitutions. For the NanoString assay, total RNA was ex- ELISA Phylogenetic tree reconstruction was performed tracted from whole blood samples collected in ELISA was performed as previously described by the neighbor-joining method (35) with the PaxGene tubes. The expression of selected (5). In brief, ELISA plates were coated with substitution model (36). Low-confidence branches genes was determined by NanoString meth- recombinant human interferon-a (rhIFN-a) (<50%) are likely to be due to gene conversion ods and a 28-gene type I IFN score was calcu- or rhIFN-w and incubated with 1:50 dilu- events between IFNA genes, as previously re- lated (44). tions of plasma samples from the patients or ported (24, 37). The tree was then visualized controls. A similar protocol was used when (38). Very similar results were obtained with REFERENCES AND NOTES testing for 12 subtypes of IFN-a. the corresponding DNA sequences (37, 39). 1. J.-L. Casanova, L. Abel, The human genetic determinism of life-threatening infectious diseases: Genetic heterogeneity and LIPS Statistical analysis physiological homogeneity? Hum. Genet. 139, 681–694 (2020). doi: 10.1007/s00439-020-02184-w; pmid: 32462426 Levels of auto-Abs against IFN-a subtypes were Comparison of proportions were performed 2. R. Döffinger et al., Autoantibodies to interferon-g in a patient measured with LIPS, as previously described using a Fisher exact test, as implemented in R with selective susceptibility to mycobacterial infection and Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 7 of 12 RES EARCH | R E S E A R C H A R T I C L E organ-specific autoimmunity. Clin. Infect. Dis. 38, e10–e14 27. A. Harris, J. Collins, D. Vetrie, C. Cole, M. Bobrow, X M. C. García Guerrero; I. Erkizia; E. Grau; M. Massanella from IrsiCaixa (2004). doi: 10.1086/380453; pmid: 14679469 inactivation as a mechanism of selection against lethal alleles: AIDS Research Institute, Badalona, Spain; and J. Guitart from 3. C. Höflich et al., Naturally occurring anti–IFN-g autoantibody Further investigation of incontinentia pigmenti and X linked the Department of Clinical Genetics, University Hospital Germans Trias and severe infections with Mycobacterium cheloneae and lymphoproliferative disease. J. Med. Genet. 29, 608–614 i Pujol, Badalona, Spain, for providing samples. We also thank Burkholderia cocovenenans. Blood 103, 673–675 (2004). (1992). doi: 10.1136/jmg.29.9.608; pmid: 1404291 J. Dalmau from IrsiCaixa for assistance. Funding: The Laboratory doi: 10.1182/blood-2003-04-1065; pmid: 12947000 28. D. Blanco-Melo et al., Imbalanced Host Response to SARS- of Human Genetics of Infectious Diseases is supported by the 4. B. Kampmann et al., Acquired predisposition to mycobacterial CoV-2 Drives Development of COVID-19. Cell 181, 1036–1045. Howard Hughes Medical Institute, The Rockefeller University, the disease due to autoantibodies to IFN-g. J. Clin. Invest. 115, e9 (2020). doi: 10.1016/j.cell.2020.04.026; pmid: 32416070 St. Giles Foundation, the National Institutes of Health (NIH) 2480–2488 (2005). doi: 10.1172/JCI19316; pmid: 16127458 29. S. L. Klein et al., Sex, age, and hospitalization drive antibody responses (R01AI088364), the National Center for Advancing Translational 5. A. Puel et al., Recurrent staphylococcal cellulitis and in a COVID-19 convalescent plasma donor population. J. Clin. Invest. Sciences (NCATS), NIH Clinical and Translational Science Award subcutaneous abscesses in a child with autoantibodies against 142004 (2020). doi: 10.1172/JCI142004; pmid: 32764200 (CTSA) program (UL1 TR001866), a Fast Grant from Emergent IL-6. J. Immunol. 180, 647–654 (2008). doi: 10.4049/ 30. T. T. Wang, J. V. Ravetch, Functional diversification of IgGs Ventures, the Mercatus Center at George Mason University, the jimmunol.180.1.647; pmid: 18097067 through Fc glycosylation. J. Clin. Invest. 129, 3492–3498 Yale Center for Mendelian Genomics and the GSP Coordinating 6. A. Puel et al., Autoantibodies against IL-17A, IL-17F, and IL-22 (2019). doi: 10.1172/JCI130029; pmid: 31478910 Center funded by the National Human Genome Research Institute in patients with chronic mucocutaneous candidiasis and 31. P. D. Burbelo et al., Sensitivity in Detection of Antibodies to (NHGRI) (UM1HG006504 and U24HG008956), the French National autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, Nucleocapsid and Spike Proteins of Severe Acute Respiratory Research Agency (ANR) under the Investments for the Future 291–297 (2010). doi: 10.1084/jem.20091983; pmid: 20123958 Syndrome Coronavirus 2 in Patients With Coronavirus Disease program (ANR-10-IAHU-01), the Integrative Biology of Emerging 7. K. Kisand et al., Chronic mucocutaneous candidiasis in 2019. J. Infect. Dis. 222, 206–213 (2020). doi: 10.1093/infdis/ Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62- APECED or thymoma patients correlates with autoimmunity to jiaa273; pmid: 32427334 IBEID), the French Foundation for Medical Research (FRM) Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010). 32. S. Meyer et al., AIRE-Deficient Patients Harbor Unique High- (EQU201903007798), the FRM and ANR GENCOVID project doi: 10.1084/jem.20091669; pmid: 20123959 Affinity Disease-Ameliorating Autoantibodies. Cell 166, 582–595 (ANRS-COV05), the Square Foundation, Grandir – Fonds de 8. C.-L. Ku, C.-Y. Chi, H. von Bernuth, R. Doffinger, Autoantibodies (2016). doi: 10.1016/j.cell.2016.06.024; pmid: 27426947 solidarité pour l’enfance, the SCOR Corporate Foundation for against cytokines: Phenocopies of primary 33. K. Katoh, J. Rozewicki, K. D. Yamada, MAFFT online service: Science, the Institut Institut National de la Santé et de la immunodeficiencies? Hum. Genet. 139, 783–794 (2020). Multiple sequence alignment, interactive sequence choice and Recherche Médicale (INSERM), and the University of Paris. doi: 10.1007/s00439-020-02180-0; pmid: 32419033 visualization. Brief. Bioinform. 20, 1160–1166 (2019). Samples from San Raffaele Hospital were obtained through the 9. A. Isaacs, J. Lindenmann, Virus interference. I. The interferon. doi: 10.1093/bib/bbx108; pmid: 28968734 Covid-BioB project and by healthcare personnel of San Raffaele Proc. R. Soc. Lond. B 147, 258–267 (1957). doi: 10.1098/ 34. K. Katoh, K. Kuma, H. Toh, T. Miyata, MAFFT version 5: Improvement Hospital, San Raffaele Telethon Institute for Gene Therapy rspb.1957.0048; pmid: 13465720 in accuracy of multiple sequence alignment. Nucleic Acids Res. 33, (SR-TIGET) clinical laboratory and clinical research unit, funded 10. A. Isaacs, J. Lindenmann, R. C. Valentine, Virus interference. II. 511–518 (2005). doi: 10.1093/nar/gki198; pmid: 15661851 by the Program Project COVID-19 OSR-UniSR and Fondazione Some properties of interferon. Proc. R. Soc. Lond. B 147, 35. N. Saitou, M. Nei, The neighbor-joining method: A new method Telethon. The French COVID Cohort Study Group was sponsored 268–273 (1957). doi: 10.1098/rspb.1957.0049; pmid: 13465721 for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, by INSERM and supported by the REACTing consortium and by a 11. I. Gresser, Wherefore interferon? J. Leukoc. Biol. 61, 567–574 406–425 (1987). doi: 10.1093/oxfordjournals.molbev.a040454; grant from the French Ministry of Health (PHRC 20-0424). The (1997). doi: 10.1002/jlb.61.5.567; pmid: 9129205 pmid: 3447015 Cov-Contact Cohort was supported by the REACTing consortium, 12. H.-H. Hoffmann, W. M. Schneider, C. M. Rice, Interferons and 36. D. T. Jones, W. R. Taylor, J. M. Thornton, The rapid generation the French Ministry of Health, and the European Commission viruses: An evolutionary arms race of molecular interactions. of mutation data matrices from protein sequences. Comput. (RECOVER WP 6). The Milieu Intérieur Consortium was supported Trends Immunol. 36, 124–138 (2015). doi: 10.1016/ Appl. Biosci. 8, 275–282 (1992). doi: 10.1093/bioinformatics/ by the French Government’s Investissement d’Avenir program, j.it.2015.01.004; pmid: 25704559 8.3.275; pmid: 1633570 Laboratoire d’Excellence Milieu Intérieur grant (ANR-10-LABX-69-01) 13. N. A. de Weerd, J. P. Vivian, S. S. Lim, S. U.-S. Huang, 37. C. H. Woelk, S. D. W. Frost, D. D. Richman, P. E. Higley, (primary investigators: L.Q.-M. and D.Du.). The Simoa P. J. Hertzog, Structural integrity with functional plasticity: S. L. Kosakovsky Pond, Evolution of the interferon alpha gene experiment was supported by the PHRC-20-0375 COVID-19 grant What type I IFN receptor polymorphisms reveal. J. Leukoc. Biol. family in eutherian mammals. Gene 397, 38–50 (2007). “DIGITAL COVID” (primary investigator: G.G.). S.G.T. is supported Downloaded from https://www.science.org on February 24, 2022 108, 909–924 (2020). doi: 10.1002/JLB.2MR0420-152R doi: 10.1016/j.gene.2007.03.018; pmid: 17512142 by a Leadership 3 Investigator Grant awarded by the National 14. J. E. Darnell Jr., STATs and gene regulation. Science 277, 38. M. V. Han, C. M. Zmasek, phyloXML: XML for evolutionary Health and Medical Research Council of Australia and a COVID19 1630–1635 (1997). doi: 10.1126/science.277.5332.1630; biology and comparative genomics. BMC Bioinformatics 10, Rapid Response Grant awarded by UNSW Sydney. C.R.-G. and pmid: 9287210 356 (2009). doi: 10.1186/1471-2105-10-356; pmid: 19860910 colleagues were supported by the Instituto de Salud Carlos III 15. A. Vallbracht, J. Treuner, B. Flehmig, K. E. Joester, 39. S. Pestka, C. D. Krause, M. R. Walter, Interferons, interferon-like (COV20_01333 and COV20_01334, Spanish Ministry of Science D. Niethammer, Interferon-neutralizing antibodies in a patient cytokines, and their receptors. Immunol. Rev. 202, 8–32 (2004). and Innovation RTC-2017-6471-1; AEI/FEDER, UE) and Cabildo treated with human fibroblast interferon. Nature 289, 496–497 doi: 10.1111/j.0105-2896.2004.00204.x; pmid: 15546383 Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas (1981). doi: 10.1038/289496a0; pmid: 6162104 40. D. M. Rissin et al., Single-molecule enzyme-linked immunosorbent del ITER para colaborar en la lucha contra la COVID-19”). S.T.-A. 16. A. Meager et al., Anti-interferon autoantibodies in autoimmune assay detects serum proteins at subfemtomolar concentrations. and A.B. were supported by ANR-20-COVI-0064 (primary polyendocrinopathy syndrome type 1. PLOS Med. 3, e289 Nat. Biotechnol. 28, 595–599 (2010). doi: 10.1038/nbt.1641; investigator: A.Be.). This work is supported by the French Ministry (2006). doi: 10.1371/journal.pmed.0030289; pmid: 16784312 pmid: 20495550 of Health “Programme Hospitalier de Recherche Clinique Inter 17. S. Panem, I. J. Check, D. Henriksen, J. Vilcek, Antibodies to 41. A. Mathian et al., Monitoring Disease Activity in Systemic regional 2013,” by the Contrat de Plan Etat-Lorraine and FEDER alpha-interferon in a patient with systemic lupus Lupus Erythematosus With Single-Molecule Array Digital Lorraine, and by a public grant overseen by the French National erythematosus. J. Immunol. 129, 1–3 (1982). pmid: 6177744 Enzyme-Linked Immunosorbent Assay Quantification of Serum Research Agency (ANR) as part of the second Investissements 18. Q. Zhang et al., Inborn errors of type I IFN immunity in Interferon-a. Arthritis Rheumatol. 71, 756–765 (2019). d’Avenir program FIGHT-HF (reference no. ANR-15-RHU-0004) and patients with life-threatening COVID-19. Science 370, doi: 10.1002/art.40792; pmid: 30507062 by the French PIA project “Lorraine Université d’Excellence” eabd4570 (2020). doi: 10.1126/science.abd4570 42. P. Lebon, G. Ponsot, J. Aicardi, F. Goutières, M. Arthuis, Early (reference no. ANR-15-IDEX-04-LUE) (45); and biobanking is 19. B. Pozzetto, K. E. Mogensen, M. G. Tovey, I. Gresser, intrathecal synthesis of interferon in herpes encephalitis. performed by the Biological Resource Center Lorrain BB-0033- Characteristics of autoantibodies to human interferon in a Biomedicine 31, 267–271 (1979). pmid: 94549 00035. This study was supported by the Fonds IMMUNOV, for patient with varicella-zoster disease. J. Infect. Dis. 150, 43. D. F. Robbiani et al., Convergent antibody responses to Innovation in Immunopathology; by a grant from the Agence 707–713 (1984). doi: 10.1093/infdis/150.5.707; pmid: 6238105 SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 National de la Recherche (ANR-flash Covid19 “AIROCovid” to 20. J.-L. Casanova, Ion Gresser. J. Interferon Cytokine Res. 39, (2020). doi: 10.1038/s41586-020-2456-9; pmid: 32555388 F.R.-L.); and by the FAST Foundation (French Friends of Sheba Tel 317–320 (2019). doi: 10.1089/jir.2018.29015.mem 44. H. Kim et al., Development of a Validated Interferon Score Hashomer Hospital). Work in the Laboratory of Virology and 21. J. E. Walter et al., Broad-spectrum antibodies against Using NanoString Technology. J. Interferon Cytokine Res. 38, Infectious Disease was supported by NIH grants P01AI138398-S1, self-antigens and cytokines in RAG deficiency. J. Clin. Invest. 125, 171–185 (2018). doi: 10.1089/jir.2017.0127; pmid: 29638206 2U19AI111825, and R01AI091707-10S1; a George Mason University 4135–4148 (2015). doi: 10.1172/JCI80477; pmid: 26457731 45. J. P. Ferreira et al., Cohort Profile: Rationale and design of the Fast Grant; and the G. Harold and Leila Y. Mathers Charitable 22. G. Beccuti et al., A COVID-19 pneumonia case report of fourth visit of the STANISLAS cohort: a familial longitudinal Foundation. The Amsterdam UMC Covid-19 Biobank was supported autoimmune polyendocrine syndrome type 1 in Lombardy, population-based cohort from the Nancy region of France. by grants from the Amsterdam Corona Research Fund, the Italy: Letter to the editor. J. Endocrinol. Invest. 43, 1175–1177 Int. J. Epidemiol. 47, 395–395j (2018). doi: 10.1093/ije/ Dr. C.J. Vaillant Fund, and the Netherlands Organization for Health (2020). doi: 10.1007/s40618-020-01323-4; pmid: 32519200 dyx240; pmid: 29220499 Research and Development [ZonMw; NWO-Vici-Grant (grant 23. J.-L. Casanova, H. C. Su, COVID Human Genetic Effort, no. 918·19·627 to D.v.d.B.)]. This work was also supported by the A Global Effort to Define the Human Genetics of Protective ACKN OWLED GMEN TS Division of Intramural Research of the National Institute of Dental Immunity to SARS-CoV-2 Infection. Cell 181, 1194–1199 We thank the patients, their families, and healthy donors for Craniofacial Research and the National Institute of Allergy and (2020). doi: 10.1016/j.cell.2020.05.016; pmid: 32405102 placing their trust in us. We thank the French Incontinentia Infectious Diseases, National Institutes of Health, and by Regione 24. J. Manry et al., Evolutionary genetic dissection of human pigmenti association for their help and support. We thank Lombardia, Italy (project “Risposta immune in pazienti con interferons. J. Exp. Med. 208, 2747–2759 (2011). doi: 10.1084/ Y. Nemirovskaya, D. Papandrea, M. Woollett, D. Liu, C. Rivalain, COVID-19 e comorbidita”). The opinions and assertions expressed jem.20111680; pmid: 22162829 and C. Patissier for administrative assistance; D. Kapogiannis herein are those of the author(s) and do not necessarily reflect 25. S. Trouillet-Assant et al., Type I IFN immunoprofiling in (National Institute on Aging) for providing healthy donor samples; the official policy or position of the Uniformed Services University COVID-19 patients. J. Allergy Clin. Immunol. 146, 206–208.e2 and S. Xirasager, J. Barnett, X. Cheng, S. Weber, J. Danielson, or the Department of Defense. J.H. holds an Institut Imagine (2020). doi: 10.1016/j.jaci.2020.04.029; pmid: 32360285 B. Garabedian, and H. Matthews for their assistance in this study. M.D.-Ph.D. fellowship from the Fondation Bettencourt Schueller. 26. J. Hadjadj et al., Impaired type I interferon activity and We also thank R. Apps, B. Ryan, and Y. Belkaid of the CHI for J.R. is supported by the INSERM Ph.D. program (“poste d’accueil inflammatory responses in severe COVID-19 patients. Science 369, their assistance. We thank the CRB-Institut Jérôme Lejeune, Inserm”). P.Ba. was supported by the French Foundation for Medical 718–724 (2020). doi: 10.1126/science.abc6027; pmid: 32661059 CRB-BioJeL, Paris, France, for their assistance. We thank Research (FRM, EA20170638020) and the M.D.-Ph.D. program Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 8 of 12 RES EARCH | R E S E A R C H A R T I C L E of the Imagine Institute (with the support of the Fondation Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, Yeray Novoa Medina156, Esmeralda Nuñez Cuadros157, Bettencourt-Schueller). We thank the Association “Turner et vous” France. 3School of Microbiology and Group of Primary Immuno- J. Gonzalo Ocejo-Vinyals158, Zerrin Orbak159, Mehdi Oualha20, for their help and support. Sample processing at IrsiCaixa was deficiencies, University of Antioquia UdeA, Medellín, Colombia. Tayfun Özçelik160, Qiang Pan Hammarström161, Christophe Parizot138, possible thanks to the crowdfunding initiative YoMeCorono. D.C.V. Tiffany Pascreau162, Estela Paz-Artal163, Rebeca Pérez de Diego85, is supported by the Fonds de la recherche en santé du Québec NIAID-USUHS Immune Response to COVID Group Anuj Kashyap1, Aurélien Philippe164, Quentin Philippot78, Laura Planas-Serra165, clinician-scientist scholar program. K.K. was supported by the Li Ding1, Marita Bosticardo1, Qinlu Wang2, Sebastian Ochoa1, Dominique Ploin166, Julien Poissy167, Géraldine Poncelet42, Estonian Research Council grant PUT1367. We thank the GEN- Hui Liu1, Samuel D. Chauvin3, Michael Stack1, Galina Koroleva4, Marie Pouletty168, Paul Quentric138, Didier Raoult139, COVID Multicenter Study (https://sites.google.com/dbm.unisi.it/ Neha Bansal5, Clifton L. Dalgard6,7, Andrew L. Snow8 Anne-Sophie Rebillat68, Ismail Reisli169, Pilar Ricart170, gen-covid). We thank the NIAID Office of Cyber Infrastructure and Jean-Christophe Richard171, Nadia Rivet28, Jacques G. Rivière172, 1 Computational Biology, Bioinformatics and Computational Laboratory of Clinical Immunology and Microbiology, Division of Gemma Rocamora Blanch15, Carlos Rodrigo1, Carlos Rodriguez-Gallego173, Biosciences Branch (contract no. HHSN316201300006W/ Intramural Research, NIAID, NIH, Bethesda, MD, USA. 2Bioinformatics Agustí Rodríguez-Palmero174, Carolina Soledad Romero175, HHSN27200002 to MSC, Inc.), the Operations Engineering Branch and Computational Biosciences Branch, NIAID Office of Cyber Anya Rothenbuhler176, Flore Rozenberg177, Maria Yolanda Ruiz del Prado178, for developing the HGRepo system to enable streamlined access to Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, Joan Sabater Riera15, Oliver Sanchez179, Silvia Sánchez-Ramón180, the data, and the NCI Advanced Biomedical Computational Science USA. 3Laboratory of Immune System Biology, Division of Intramural Agatha Schluter165, Matthieu Schmidt181, Cyril E. Schweitzer182, (ABCS) for data transformation support. Biomedical Advanced Research, NIAID, NIH, Bethesda, MD, USA. 4NIH Center for Human Francesco Scolari183, Anna Sediva184, Luis M. Seijo185, Research and Development Authority was supported under contract Immunology, NIH, Bethesda, MD, USA. 5Multiscale Systems Biology Damien Sene13, Sevtap Senoglu114, Mikko R. J. Seppänen186, no. HHSO10201600031C (to J.H.). Financial support was provided Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, Alex Serra Ilovich187, Mohammad Shahrooei62, David Smadja188, by the National Institute of Allergy and Infectious Diseases (NIAID) MD, USA. 6PRIMER, Uniformed Services University of the Health Ali Sobh189, Xavier Solanich Moreno15, Jordi Solé-Violán190, K08AI135091; the Burroughs Wellcome Fund CAMS; the Clinical Sciences, Bethesda, MD, USA. 7Department of Anatomy, Physiology & Catherine Soler191, Pere Soler-Palacín133, Yuri Stepanovskiy192, Immunology Society; and the American Academy of Allergy, Genetics, Uniformed Services University of the Health Sciences, Annabelle Stoclin193, Fabio Taccone145, Yacine Tandjaoui-Lambiotte194, Asthma, and Immunology. Author contributions: Bethesda, MD, USA. 8Department of Pharmacology & Molecular Jean-Luc Taupin195, Simon J. Tavernier196, Benjamin Terrier197, P.Ba., L.B.R., Q.Z., E.M., H.-H.H., Y.Z., K.Dor., Q.P., J.R., V.B., J.Ma., Therapeutics, Uniformed Services University of the Health Sciences, Caroline Thumerelle105, Gabriele Tomasoni198, Julie Toubiana47, E.S., L.H., P.P., L.L., L.B., S.T.-A., K.Dob., A.A.d.J., A.Be., L.P., D.D., Bethesda, MD, USA. Josep Trenado Alvarez199, Sophie Trouillet-Assant200, E.S.H., J.S.T., R.G.-M., K.K., A.P., S.-Y.Z., S.M.H., G.G., E.J., C.M.R., Jesús Troya201, Alessandra Tucci202, Matilde Valeria Ursini84, L.D.N., H.C.S., and J.-L.C. performed or provided supervision of COVID Clinicians Jorge Abad1, Sergio Aguilera-Albesa2, Yurdagul Uzunhan203, Pierre Vabres204, Juan Valencia-Ramos205, experiments, generated and analyzed data, and contributed to the Ozge Metin Akcan3, Ilad Alavi Darazam4, Juan C. Aldave5, Ana Maria Van Den Rym85, Isabelle Vandernoot206, Hulya Vatansev207, manuscript by providing figures and tables. J.L.P., G.K., B.B., Miquel Alfonso Ramos6, Seyed Alireza Nadji7, Gulsum Alkan8, Valentina Vélez-Santamaria41, Sébastien Viel166, Cédric Vilain208, Y.S., R.Y., A.B., K.B., R.P.L., M.M., A.C., and L.A. performed Jerome Allardet-Servent9, Luis M. Allende10, Laia Alsina11, Marie- Marie E. Vilaire68, Audrey Vincent34, Guillaume Voiriot209, computational analysis of data. P.Ba., A.K., E.C., Y.T.-L., A.N.S., Alexandra Alyanakian12, Blanca Amador-Borrero13, Zahir Amoura14, Fanny Vuotto105, Alper Yosunkaya91, Barnaby E. Young123, O.M.D., M.S.A., A.A., G.C., V.L., F.C., M.V., D.M.S., J.H., B.T., D.Du., Arnau Antolí15, Sevket Arslan16, Sophie Assant17, Terese Auguet18, Fatih Yucel210, Faiez Zannad211, Mayana Zatz36, Alexandre Belot212* L.Q.-M., D.v.d.B., L.R., D.C.V., S.G.T., F.H., D.Da., T.H.M., P.Br., Axelle Azot19, Fanny Bajolle20, Aurélie Baldolli21, Maite Ballester22, J.M.-P., M.C.N., S.B.-D., C.R.-G., G.V., A.J.O., J.Gu, P.D.B., J.I.C., Hagit Baris Feldman23, Benoit Barrou24, Alexandra Beurton25, 1 University Hospital and Research Institute “Germans Trias i Pujol”, A.B., L.R.B., M.D.’A., P.Bo., P.R., F.R.-L., F.F., M.V.U., L.I., A.S., Agurtzane Bilbao26, Geraldine Blanchard-Rohner27, Ignacio Blanco1, Badalona, Spain. 2Navarra Health Service Hospital, Pamplona, S.P., E.Q.-R., C.R., R.C., D.M., A.L., G.L.M., X.D., J.Gh., M.S.L., Adeline Blandinières28, Daniel Blazquez-Gamero29, Spain. 3Division of Pediatric Infectious Diseases, Necmettin and G.G. evaluated and recruited patients to COVID and/or Marketa Bloomfield30, Mireia Bolivar-Prados31, Raphael Borie32, Erbakan University, Meram Medical Faculty, Konya, Turkey. control cohorts of patients. P.Ba. and J.-L.C. wrote the Ahmed A. Bousfiha33, Claire Bouvattier34, Oksana Boyarchuk35, 4 Department of Infectious Diseases, Loghman Hakim Hospital, manuscript. J.-L.C. supervised the project. All authors edited the Maria Rita P. Bueno36, Jacinta Bustamante20, Juan José Cáceres Shahid Beheshti University of Medical Sciences, Tehran, Iran. manuscript. Competing interests: H.C.S. is adjunct faculty at Agra37, Semra Calimli38, Ruggero Capra39, Maria Carrabba40, 5 Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru. 6Parc the University of Pennsylvania. J.-L.C. is listed as an inventor on Carlos Casasnovas41, Marion Caseris42, Martin Castelle43, Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain. patent application U.S. 63/055,155 filed by The Rockefeller Francesco Castelli44, Martín Castillo de Vera45, Mateus V. Castro36, 7 Virology Research Center, National institutes of Tuberculosis and Downloaded from https://www.science.org on February 24, 2022 University that encompasses aspects of this publication. R.P.L. is Emilie Catherinot46, Martin Chalumeau47, Bruno Charbit48, Lung diseases, Shahid Beheshti University of Medical Sciences, a nonexecutive director of Roche and its subsidiary Genentech. Matthew P. Cheng49, Père Clavé31, Bonaventura Clotet50, Tehran, Iran. 8Division of Pediatric Infectious Diseases, Faculty of The authors declare no other competing interests. Data and Anna Codina51, Fatih Colkesen52, Fatma Colkesen53, Roger Colobran 54, Medicine, Selcuk University, Konya, Turkey. 9Intensive Care Unit, materials availability: All data are available in the manuscript or Cloé Comarmond55, Angelo G. Corsico56, David Dalmau57, Hôpital Européen, Marseille, France. 10Immunology Department, in the supplementary materials. Plasma, cells, and genomic DNA David Ross Darley58, Nicolas Dauby59, Stéphane Dauger60, University Hospital 12 de Octubre, Research Institute imas12, are available from J.-L.C. or D.C.V. under a material transfer Loic de Pontual61, Amin Dehban62, Geoffroy Delplancq63, Complutense University, Madrid, Spain. 11Hospital Sant Joan de agreement with The Rockefeller University and the Research Alexandre Demoule64, Antonio Di Sabatino65, Jean-Luc Diehl66, Déu, Barcelona, Spain. 12Department of Biological Immunology, Institute-McGill University Health Centre. Huh7.5 cells are available Stephanie Dobbelaere67, Sophie Durand68, Waleed Eldars69, Necker Hospital for Sick Children, APHP and INEM, Paris, France. on request from C.M.R. under a material transfer agreement Mohamed Elgamal70, Marwa H. Elnagdy71, Melike Emiroglu72, 13 Internal Medicine Department, Hôpital Lariboisière, APHP; with The Rockefeller University and Apath, LLC. Materials and Emine Hafize Erdeniz73, Selma Erol Aytekin74, Romain Euvrard75, Université de Paris, Paris, France. 14Internal Medicine Department, reagents used are almost exclusively commercially available and Recep Evcen76, Giovanna Fabio40, Laurence Faivre77, Pitié-Salpétrière Hospital, Paris, France. 15Hospital Universitari de nonproprietary. Requests for materials derived from human Antonin Falck42, Muriel Fartoukh78, Morgane Faure79, Bellvitge, Barcelona, Spain. 16Division of Clinical Immunology and samples may be made available, subject to any underlying Miguel Fernandez Arquero80, Carlos Flores81, Bruno Francois82, Allergy, Necmettin Erbakan University, Meram Medical Faculty, restrictions on such samples. J.-L.C. can make material transfer Victoria Fumadó83, Francesca Fusco84, Blanca Garcia Solis85, Konya, Turkey. 17Joint Research Unit, Hospices Civils de Lyon-bio agreements available through The Rockefeller University. This work Pascale Gaussem86, Juana Gil-Herrera87, Laurent Gilardin88, Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Lyon, France. is licensed under a Creative Commons Attribution 4.0 International Monica Girona Alarcon89, Mónica Girona-Alarcón89, 18 Hospital Universitario de Tarragona Joan XXIII, Universitat Rovira (CC BY 4.0) license, which permits unrestricted use, distribution, Jean-Christophe Goffard90, Funda Gok91, Rafaela González-Montelongo92, i Virgili (URV), IISPV, Tarragona, Spain. 19Private practice, Paris, and reproduction in any medium, provided the original work is Antoine Guerder93, Yahya Gul94, Sukru Nail Guner94, Marta Gut95, France. 20Necker Hospital for Sick Children, AP-HP, Paris, France. properly cited. To view a copy of this license, visit https:// Jérôme Hadjadj96, Filomeen Haerynck97, Rabih Halwani98, 21 Department of Infectious Diseases, CHU de Caen, Caen, creativecommons.org/licenses/by/4.0/. This license does not Lennart Hammarström99, Nevin Hatipoglu100, Elisa Hernandez-Brito101, France. 22Consorcio Hospital General Universitario, Valencia, Spain. apply to figures/photos/artwork or other content included in the María Soledad Holanda-Peña102, Juan Pablo Horcajada103, 23 The Genetics Institute, Tel Aviv Sourasky Medical Center and article that is credited to a third party; obtain authorization from Sami Hraiech104, Linda Humbert105, Alejandro D. Iglesias106, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. the rights holder before using such material. Antonio Íñigo-Campos92, Matthieu Jamme107, María Jesús 24 Department of Urology, Nephrology, Transplantation, APHP-SU, Arranz108, Iolanda Jordan109, Fikret Kanat110, Hasan Kapakli111, Sorbonne Université, INSERM U 1082, Paris, France. 25Service de SUPPLEMENTARY MATERIALS Iskender Kara112, Adem Karbuz113, Kadriye Kart Yasar114, Médecine Intensive–Réanimation et Pneumologie, APHP Hôpital science.sciencemag.org/content/370/6515/eabd4585/suppl/DC1 Sevgi Keles115, Yasemin Kendir Demirkol116, Adam Klocperk117, Pitié–Salpêtrière, Paris, France. 26Cruces University Hospital, Supplementary Materials and Methods Zbigniew J. Król118, Paul Kuentz119, Yat Wah M. Kwan120, Bizkaia, Spain. 27Paediatric Immunology and Vaccinology Unit, Figs. S1 to S4 Jean-Christophe Lagier121, Yu-Lung Lau122, Fleur Le Bourgeois60, Geneva University Hospitals and Faculty of Medicine, Geneva, Tables S1 to S3 Yee-Sin Leo123, Rafael Leon Lopez124, Daniel Leung122, Switzerland. 28Hematology, Georges Pompidou Hospital, APHP, Data S1 Michael Levin125, Michael Levy60, Romain Lévy20, Zhi Li48, Paris, France. 29Pediatric Infectious Diseases Unit, Instituto de Agnes Linglart126, José M. Lorenzo-Salazar92, Céline Louapre127, Investigación 12 de Octubre (imas12), Hospital Universitario 12 de View/request a protocol for this paper from Bio-protocol. Catherine Lubetzki127, Charles-Edouard Luyt128, David C. Lye129, Octubre, Madrid, Spain. 30Department of Immunology, Motol Davood Mansouri130, Majid Marjani131, Jesus Marquez Pereira132, University Hospital, 2nd Faculty of Medicine, Charles University, HGID Lab Andrés Augusto Arias1,3, Bertrand Boisson1,2, Andrea Martin133, David Martínez Pueyo134, Javier Martinez- Department of Pediatrics, Thomayer’s Hospital, 1st Faculty of Soraya Boucherit2, Jacinta Bustamante1,2, Marwa Chbihi2, Picado135, Iciar Marzana136, Alexis Mathian14, Larissa R. B. Matos36, Medicine, Charles University, Prague, Czech Republic. 31Centro de Jie Chen1, Maya Chrabieh2, Tatiana Kochetkov1, Tom Le Voyer2, Gail V. Matthews137, Julien Mayaux138, Jean-Louis Mège139, Investigación Biomédica en Red de Enfermedades Hepàticas y Dana Liu1, Yelena Nemirovskaya1, Masato Ogishi1, Isabelle Melki140, Jean-François Meritet141, Ozge Metin142, Digestivas (Ciberehd), Hospital de Mataró, Consorci Sanitari del Dominick Papandrea1, Cécile Patissier2, Franck Rapaport1, Isabelle Meyts143, Mehdi Mezidi144, Isabelle Migeotte145, Maresme, Mataró, Spain. 32Service de Pneumologie, Hopital Bichat, Manon Roynard2, Natasha Vladikine2, Mark Woollett1, Peng Zhang1 Maude Millereux146, Tristan Mirault147, Clotilde Mircher68, APHP, Paris, France. 33Clinical Immunology Unit, Pediatric Mehdi Mirsaeidi148, Abián Montesdeoca Melián149, Infectious Disease Department, Faculty of Medicine and Pharmacy, 1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Antonio Morales Martinez150, Pierre Morange151, Clémence Mordacq105, Averroes University Hospital, LICIA Laboratoire d'immunologie Rockefeller Branch, The Rockefeller University, New York, NY, USA. Guillaume Morelle152, Stéphane Mouly13, Adrián Muñoz-Barrera92, clinique, d'inflammation et d'allergie, Hassann Ii University, 2 Laboratory of Human Genetics of Infectious Diseases, Necker Cyril Nafati153, João Farela Neves154, Lisa F. P. Ng155, Casablanca, Morocco. 34Endocrinology Unit, APHP Hôpitaux Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 9 of 12 RES EARCH | R E S E A R C H A R T I C L E Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. 35Department Brussels, Belgium. 91Division of Critical Care Medicine, Department 147 Vascular Medicine, Georges Pompidou Hospital, APHP, Paris, of Children's Diseases and Pediatric Surgery, I.Horbachevsky of Anesthesiology and Reanimation, Necmettin Erbakan University, France. 148Division of Pulmonary and Critical Care, University of Ternopil National Medical University, Ternopil, Ukraine. 36Human Meram Medical Faculty, Konya, Turkey. 92Genomics Division, Miami, Miami, FL, USA. 149Guanarteme Health Care Center, Genome and Stem-Cell Research Center, University of São Paulo, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz Canarian Health System, Las Palmas de Gran Canaria, Spain. São Paulo, Brazil. 37Hospital Insular, Las Palmas de Gran Canaria, de Tenerife, Spain. 93Assistance Publique Hôpitaux de Paris, Paris, 150 Regional University Hospital of Málaga, Málaga, Spain. 151Aix- Spain. 38Division of Critical Care Medicine, Department of France. 94Division of Allergy and Immunology, Necmettin Erbakan Marseille Université, Marseille, France. 152Department of General Anesthesiology and Reanimation, Konya State Hospital, Konya, University, Meram Medical Faculty, Konya, Turkey. 95CNAG-CRG, Paediatrics, Hôpital Bicêtre, AP-HP, University of Paris Saclay, Le Turkey. 39MS Center, Spedali Civili, Brescia, Italy. 40Fondazione Centre for Genomic Regulation (CRG), Barcelona Institute of Kremlin-Bicêtre, France. 153CHU de La Timone, Marseille, France. 154 IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Science and Technology (BIST); Universitat Pompeu Fabra (UPF), Centro Hospitalar Universitário de Lisboa Central, Lisbon, 41 Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain. 96Department of Internal Medicine, National Portugal. 155Infectious Diseases Horizontal Technlogy Centre, Barcelona, Spain. 42Hopital Robert Debré, Paris, France. 43Pediatric Reference Center for Rare Systemic Autoimmune Diseases, A*STAR; Singapore Immunology Network, A*STAR, Singapore. Immuno-hematology Unit, Necker Enfants Malades Hospital, AP-HP, APHP-CUP, Hôpital Cochin, Paris, France. 97Ghent Univer- 156 Department of Pediatrics, Complejo Hospitalario Universitario AP-HP, Paris, France. 44Department of Infectious and Tropical sity Hospital, Ghent, Belgium. 98Sharjah Institute of Medical Insular-Materno Infantil, Canarian Health System, Las Palmas de Diseases, University of Brescia, ASST Spedali Civili di Brescia, Research, College of Medicine, University of Sharjah, Sharjah, Gran Canaria, Spain. 157Regional University Hospital of Málaga, Brescia, Italy. 45Doctoral Health Care Center, Canarian Health United Arab Emirates. 99Department of Biosciences and Nutrition, Málaga, Spain. 158Hospital Universitario Marqués de Valdecilla, System, Las Palmas de Gran Canaria, Spain. 46Hôpital Foch, SE14183, Huddinge, Karolinska Institutet, Stockholm, Sweden. Santander, Spain. 159Ataturk University Medical Faculty, Erzurum, Suresnes, France. 47Necker Hospital for Sick Children, Paris 100 Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Konuk Turkey. 160Bilkent University, Department of Molecular Biology and University, AP-HP, Paris, France. 48Pasteur Institute, Paris, France. Training and Research Hospital, University of Health Sciences, Genetics, Ankara, Turkey. 161Department of Laboratory Medicine, 49 McGill University Health Centre, Montreal, Canada. 50University Istanbul, Turkey. 101Department of Immunology, Hospital Universi- Karolinska Institutet, SE14186, Stockholm, Sweden. 162L'Hôpital Hospital and Research Institute “Germans Trias i Pujol”, IrsiCaixa tario de Gran Canaria Dr. Negrín, Canarian Health System, Las Foch, Suresnes, France. 163Department of Immunology, Hospital AIDS Research Institute, UVic-UCC, Badalona, Spain. 51Clinical Palmas de Gran Canaria, Spain. 102Intensive Care Unit, Marqués de Universitario 12 de Octubre, Instituto de Investigación Sanitaria Biochemistry, Pathology, Paediatric Neurology and Molecular Valdecilla Hospital, Santander, Spain. 103Hospital del Mar, Parc de Hospital 12 de Octubre (imas12), Madrid, Spain. 164APHP Hôpitaux Medicine Departments and Biobank, Institut de Recerca Sant Joan Salut Mar, Barcelona, Spain. 104Intensive Care Unit, APHM, Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. 165Neuro- de Déu and CIBERER-ISCIII, Esplugues, Spain. 52Division of Clinical Marseille, France. 105CHU Lille, Lille, France. 106Department of metabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, Immunology and Allergy, Department of Internal Medicine, Pediatrics, Columbia University, New York, NY, USA. 107Centre Barcelona; CIBERER U759, ISCiii, Madrid, Spain. 166Hospices Civils Necmettin Erbakan University, Meram Medical Faculty, Konya, Hospitalier Intercommunal Poissy Saint Germain en Laye, Poissy, de Lyon, Lyon, France. 167Université de Lille, Inserm U1285, CHU Turkey. 53Department of Infectious Diseases and Clinical Micro- France. 108Fundació Docència i Recerca Mútua Terrassa, Barcelona, Lille, Paris, France. 168Department of General Pediatrics, University biology, Konya Training and Research Hospital, Konya, Turkey. Spain. 109Hospital Sant Joan de Déu, Kids Corona Platfform, Hospital Robert Debré, APHP, Paris, France. 169Necmettin Erbakan 54 Hospital Universitari Vall d’Hebron, Barcelona, Spain. Barcelona, Spain. 110Selcuk University, Faculty of Medicine, Chest University, Konya, Turkey. 170Germans Trias i Pujol Hospital, 55 Pitié-Salpêtrière Hospital, Paris, France. 56Respiratory Diseases Diseases Department, Konya, Turkey. 111Division of Allergy and Badalona, Spain. 171Medical Intensive Care Unit, Hopital de la Division, IRCCS Policlinico San Matteo Foundation and University of Immunology, Balikesir Ataturk City Hospital, Balikesir, Turkey. Croix-Rousse, Hospices Civils de Lyon, Lyon, France. 172Pediatric Pavia, Pavia, Italy. 57Fundació Docència i Recerca Mútua Terrassa, 112 Division of Critical Care Medicine, Selcuk University, Faculty of Infectious Diseases and Immunodeficiencies Unit, Hospital Uni- Barcelona, Spain. 58UNSW Medicine, St Vincent's Clinical School; Medicine, Konya, Turkey. 113Division of Pediatric Infectious versitari Vall d’Hebron, Vall d'Hebron Research Institute, Vall Department of Thoracic Medicine, St Vincent's Hospital Darling- Diseases, Prof. Dr. Cemil Tascıoglu City Hospital, Istanbul, Turkey. d’Hebron Barcelona Hospital Campus, Barcelona, Spain. hurst, Sidney, Australia. 59CHU Saint-Pierre, Université Libre de 114 Departments of Infectious Diseases and Clinical Microbiology, 173 Department of Immunology, Hospital Universitario de Gran Bruxelles (ULB), Brussels, Belgium. 60Pediatric Intensive Care Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Robert-Debré University Hospital, APHP, Paris, France. 61Sorbonne of Health Sciences, Istanbul, Turkey. 115Meram Medical Faculty, Canaria, Spain; University Fernando Pessoa Canarias, Las Palmas Paris Nord, Hôpital Jean Verdier, APHP, Bondy, France. Necmettin Erbakan University, Meram Medical Faculty, Konya, de Gran Canaria, Spain. 174Neurometabolic Diseases Laboratory, 62 Specialized Immunology Laboratory of Dr. Shahrooei, Sina Turkey. 116Health Sciences University, Umraniye Education and IDIBELL-Hospital Duran i Reynals, Barcelona, Spain. 175Consorcio Medical Complex, Ahvaz, Iran. 63Centre de génétique humaine, Research Hospital, Istanbul, Turkey. 117Department of Immunology, Hospital General Universitario, Valencia, Spain. 176APHP Hôpitaux Downloaded from https://www.science.org on February 24, 2022 CHU Besançon, Besançon, France. 64Sorbonne Université 2nd Faculty of Medicine, Charles University and University Hospital Universitaires Paris-Sud, Paris, France. 177Virology Unit, Université Médecine and APHP Sorbonne Université site Pitié-Salpêtrière, in Motol, Prague, Czech Republic. 118Central Clinical Hospital of de Paris, Cohin Hospital, APHP, Paris, France. 178Hospital San Paris, France. 65Department of Internal Medicine, Fondazione Ministry of the Interior and Administration in Warsaw, Warsaw, Pedro, Logroño, Spain. 179Respiratory medicine, Georges Pompidou IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy. Poland. 119Oncobiologie Génétique Bioinformatique, PC Bio, CHU Hospital, APHP, Paris, France. 180Department of Immunology, 66 Intensive Care Unit, Georges Pompidou Hospital, APHP, Paris, Besançon, Besançon, France. 120Paediatric Infectious Disease Unit, Hospital Clínico San Carlos, Madrid, Spain. 181Service de Médecine France. 67Department of Pneumology, AZ Delta, Roeselare, Hospital Authority Infectious Disease Center, Princess Margaret Intensive Réanimation, Institut de Cardiologie, Hopital Pitié- Belgium. 68Institut Jérôme Lejeune, Paris, France. 69Department of Hospital, Hong Kong (Special Administrative Region), China. 121Aix Salpêtrière, Paris, France. 182CHRU de Nancy, Hôpital d'Enfants, Microbiology and Immunology, Faculty of Medicine, Mansoura Marseille Univ, IRD, MEPHI, IHU Méditerranée Infection, Marseille, Vandoeuvre, France. 183Chair of Nephrology, University of Brescia, University, Mansoura, Egypt. 70Department of Chest, Faculty of France. 122Department of Paediatrics and Adolescent Medicine, The Brescia, Italy. 184Department of Immunology, 2nd Faculty of Medicine, Mansoura University, Mansoura, Egypt. 71Department of University of Hong Kong, Hong Kong, China. 123National Centre for Medicine, Charles University and Motol University Hospital, Prague, Medical Biochemistry and Molecular Biology, Faculty of Medicine, Infectious Diseases, Singapore. 124Hospital Universitario Reina Czech Republic. 185Clínica Universidad de Navarra, Madrid, Spain. Mansoura University, Mansoura, Egypt. 72Faculty of Medicine, Sofía, Cordoba, Spain. 125Imperial College, London, UK. 126Endo- 186 HUS Helsinki University Hospital, Children and Adolescents, Division of Pediatric Infectious Diseases, Selcuk University, Konya, crinology and diabetes for children, AP-HP, Bicêtre Paris-Saclay Rare Disease Center, and Inflammation Center, Adult Immuno- Turkey. 73Division of Pediatric Infectious Diseases, Ondokuz Mayıs Hospital, Le Kremlin-Bicêtre, France. 127Neurology Unit, APHP deficiency Unit, Majakka, Helsinki, Finland. 187Fundació Docència i University, Samsun, Turkey. 74Necmettin Erbakan University, Pitié-Salpêtrière Hospital, Paris University, Paris, France. 128Inten- Recerca Mútua Terrassa, Terrassa, Spain. 188Hopital Européen Meram Medical Faculty, Division of Pediatric Allergy and Immu- sive Care Unit, APHP Pitié-Salpêtrière Hospital, Paris University, Georges Pompidou, Paris, France. 189Department of Pediatrics, nology, Konya, Turkey. 75Centre Hospitalier Fleyriat, Bourg-en- Paris, France. 129National Centre for Infectious Diseases; Tan Tock Faculty of Medicine, Mansoura University, Mansoura, Egypt. Bresse, France. 76Division of Clinical Immunology and Allergy, Seng Hospital; Yong Loo Lin School of Medicine; Lee Kong Chian 190 Critical Care Unit, Hospital Universitario de Gran Canaria Dr. Department of Internal Medicine, Necmettin Erbakan University, School of Medicine, Singapore. 130Department of Clinical Immu- Negrín, Canarian Health System, Las Palmas de Gran Canaria, Meram Medical Faculty, Konya, Turkey. 77Centre de Génétique, nology and Infectious Diseases, National Research Institute of Spain. 191CHU de Saint Etienne, Saint-Priest-en-Jarez, France. CHU Dijon, Dijon, France. 78APHP Tenon Hospital, Paris, France. Tuberculosis and Lung Diseases, Shahid Beheshti University of 192 Shupyk National Medical Academy for Postgraduate Education, 79 Sorbonne Universités, UPMC University of Paris, Paris, France. Medical Sciences, Tehran, Iran. 131Clinical Tuberculosis and Kiev, Ukraine. 193Gustave Roussy Cancer Campus, Villejuif, France. 80 194 Department of Clinical Immunology, Hospital Clínico San Carlos, Epidemiology Research Center, National Research Institute of Intensive Care Unit, Avicenne Hospital, APHP, Bobigny, France. Madrid, Spain. 81Genomics Division, Instituto Tecnológico y de Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti 195 Laboratory of Immunology and Histocompatibility, Saint-Louis Energías Renovables (ITER), Santa Cruz de Tenerife, Spain; CIBER University of Medical Sciences, Tehran, Iran. 132Hospital Sant Joan Hospital, Paris University, Paris, France. 196Department of Internal de Enfermedades Respiratorias, Instituto de Salud Carlos III, de Déu and University of Barcelona, Barcelona, Spain. 133Pediatric Diseases and Pediatrics, Primary Immune Deficiency Research Madrid, Spain; Research Unit, Hospital Universitario N.S. de Infectious Diseases and Immunodeficiencies Unit, Hospital Uni- Laboratory, Centre for Primary Immunodeficiency Ghent, Jeffrey Candelaria, Santa Cruz de Tenerife, Spain; Instituto de Tecnologías versitari Vall d’Hebron, Vall d'Hebron Research Institute, Vall Modell Diagnosis and Research Centre, Ghent University Hospital, Biomédicas (ITB), Universidad de La Laguna, San Cristóbal de La d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Ghent, Belgium. 197Department of Internal Medicine, Université de Laguna, Spain. 82CHU Limoges and Inserm CIC 1435 & UMR 1092, Barcelona (UAB), Barcelona, Spain. 134Hospital Universitari Mutua Paris, INSERM, U970, PARCC, F-75015, Paris, France. 198First Limoges, France. 83Infectious Diseases Unit, Department of de Terrassa, Universitat de Barcelona, Barcelona, Spain. Division of Anesthesiology and Critical Care Medicine, University of 135 Pediatrics, Hospital Sant Joan de Déu, Barcelona, Spain; Institut IrsiCaixa AIDS Research Institute, ICREA, UVic-UCC, Research Brescia, ASST Spedali Civili di Brescia, Brescia, Italy. 199Intensive de Recerca Sant Joan de Déu, Spain; Universitat de Barcelona Institute “Germans Trias i Pujol”, Badalona, Spain. 136Department Care Department, Hospital Universitari MutuaTerrassa, Universitat (UB), Barcelona, Spain. 84Institute of Genetics and Biophysics of Laboratory, Cruces University Hospital, Barakaldo, Bizkaia, Barcelona, Terrassa, Spain. 200Hospices Civils de Lyon, Lyon Sud ‘Adriano Buzzati-Traverso’, IGB-CNR, Naples, Italy. 85Laboratory of Spain. 137University of New South Wales, Darlinghurst, NSW, Hospital, Lyon, France. 201Infanta Leonor University Hospital, Immunogenetics of Human Diseases, IdiPAZ Institute for Health Australia. 138APHP Pitié-Salpêtrière Hospital, Paris, France. 139Aix- Madrid, Spain. 202Hematology Department, ASST Spedali Civili di Research, La Paz Hospital, Madrid, Spain. 86Hematology, APHP, Marseille University, APHM, Marseille, France. 140Robert Debré Brescia, Brescia, Italy. 203Pneumologie, Hôpital Avicenne, APHP, Hopital Européen Georges Pompidou and Inserm UMR-S1140, Hospital, Paris, France. 141APHP Cohin Hospital, Paris, France. INSERM U1272, Université Sorbonne Paris Nord, Bobigny, France. Paris, France. 87Hospital General Universitario and Instituto de 142 Necmettin Erbakan University Meram Faculty of Medicine 204 Dermatology Unit, Laboratoire GAD, INSERM UMR1231 LNC, Investigación Sanitaria WGregorio MarañónW, Madrid, Spain. 88Bégin Department of Pediatric Infectious Diseases, Konya, Turkey. Université de Bourgogne, Dijon, France. 205University Hospital of military Hospital, Bégin, France. 89Pediatric Intensive Care Unit, 143 University Hospitals Leuven, Leuven, Belgium. 144Hospices Civils Burgos, Burgos, Spain. 206Center of Human Genetics, Hôpital Hospital Sant Joan de Déu, Barcelona, Spain. 90Department of de Lyon, Hôpital de la Croix-Rousse, Lyon, France. 145Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles, Erasme, Brussels, Belgium. 146CH Gonesse, Gonesse, France. 207 Department of Chest Diseases, Necmettin Erbakan University, Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 10 of 12 RES EARCH | R E S E A R C H A R T I C L E Meram Medical Faculty, Konya, Turkey. 208CHU de Caen, Caen, 28 Bordeaux - SMIT, France. 29RENARCI, Annecy, France. Leo Heunks2, Markus W. Hollmann8, Janneke Horn2, Joppe W. Hovius1, France. 209Sorbonne Université, Service de Médecine Intensive 30 Hôpital Robert Debré, Paris, France. 31Colombes - Louis Menno D. de Jong12, Rutger Koning4, Niels van Mourik2, Jeaninne Réanimation, Hôpital Tenon, Assistance Publique-Hôpitaux de Mourier - Gynécologie, France. 32University of Lorraine, Nellen1, Frederique Paulus2, Edgar Peters1, Tom van der Poll1, Paris, Paris, France. 210General Intensive Care Unit, Konya Training Plurithematic Clinical Investigation Centre Inserm CIC-P; 1433, Benedikt Preckel8, Jan M. Prins1, Jorinde Raasveld2, Tom Reijnders1, and Research Hospital, Konya, Turkey. 211CHU de Nancy, Nancy, Inserm U1116, CHRU Nancy Hopitaux de Brabois, F-CRIN Michiel Schinkel1, Marcus J. Schultz2, Alex Schuurman13, France. 212University of Lyon, CIRI, INSERM U1111, National Referee INI-CRCT; (Cardiovascular and Renal Clinical Trialists), Nancy, Kim Sigaloff1, Marry Smit2, Cornelis S. Stijnis1, Willemke Stilma2, Centre RAISE, Pediatric Rheumatology, HFME, Hospices Civils de France. 33Inserm CIC-1414, Rennes, France. 34Institut Pasteur, Charlotte Teunissen14, Patrick Thoral2, Anissa Tsonas2, Lyon, Lyon, France. *Leader of the COVID-Clinicians group. UMR 3569 CNRS, Université de Paris, Paris, France. 35Hôpital la Marc van der Valk1, Denise Veelo8, Alexander P. J. Vlaar15, timone, Marseille, France. 36Paris - Bichat - SMIT, France. Heder de Vries2, Michèle van Vugt1, W. Joost Wiersinga1, COVID-STORM Clinicians Giuseppe Foti1, Giacomo Bellani1, Dorien Wouters16, A. H. (Koos) Zwinderman17, Diederik van de Beek18* Giuseppe Citerio1, Ernesto Contro1, Alberto Pesci2, Maria Grazia The Milieu Intérieur Consortium Laurent Abel1, Andres Alcover2, Valsecchi3, Marina Cazzaniga4 Hugues Aschard2, Kalla Astrom3, Philippe Bousso2, Pierre Bruhns2, 1 Department of Infectious Diseases, Amsterdam UMC, Amsterdam, Ana Cumano2, Caroline Demangel2, Ludovic Deriano2, Netherlands. 2Department of Intensive Care, Amsterdam UMC, 1 Department of Emergency, Anesthesia and Intensive Care, School James Di Santo2, Françoise Dromer2, Gérard Eberl2, Jost Enninga2, Amsterdam, Netherlands. 3Experimental Immunology, Amsterdam of Medicine and Surgery, University of Milano-Bicocca, San Jacques Fellay4, Ivo Gomperts-Boneca2, Milena Hasan2, UMC, Amsterdam, Netherlands. 4Department of Neurology, Gerardo Hospital, Monza, Italy. 2Department of Pneumology, Serge Hercberg5, Olivier Lantz6, Hugo Mouquet2, Etienne Patin2, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Netherlands. School of Medicine and Surgery, University of Milano-Bicocca, San Sandra Pellegrini2, Stanislas Pol7, Antonio Rausell8, Lars Rogge2, 5 Department of Pulmonology, Amsterdam UMC, Amsterdam, Gerardo Hospital, Monza, Italy. 3Center of Bioinformatics and Anavaj Sakuntabhai2, Olivier Schwartz2, Benno Schwikowski2, Netherlands. 6Department of Infectious Diseases, Amsterdam UMC, Biostatistics, School of Medicine and Surgery, University of Milano- Spencer Shorte2, Frédéric Tangy2, Antoine Toubert9, Amsterdam, Netherlands. 7Department of Pathology, Amsterdam Bicocca, San Gerardo Hospital, Monza, Italy. 4Phase I Research Mathilde Touvier10, Marie-Noëlle Ungeheuer2, Matthew L. Albert11*, UMC, Amsterdam, Netherlands. 8Department of Anesthesiology, Center, School of Medicine and Surgery, University of Darragh Duffy2*, Lluis Quintana-Murci2* Amsterdam UMC, Amsterdam, Netherlands. 9Department of Milano-Bicocca, San Gerardo Hospital, Monza, Italy. Experimental Immunology, Amsterdam UMC, Amsterdam, 1 INSERM U1163, University of Paris, Imagine Institute, Paris, Netherlands. 10Amsterdam UMC, Netherlands Biobank Core Imagine COVID Group Christine Bole-Feysot1, Stanislas Lyonnet1*, France. 2Pasteur Institute, Paris, France. 3Lund University, Lund, Facility, Amsterdam UMC, Amsterdam, Netherlands. 11Department Cécile Masson1, Patrick Nitschke1, Aurore Pouliet1, Yoann Schmitt1, Sweden. 4EPFL, Lausanne, Switzerland. 5Université Paris 13, Paris, of Radiology, Amsterdam UMC, Amsterdam, Netherlands. Frederic Tores1, Mohammed Zarhrate1 France. 6Curie Institute, Paris, France. 7Cochin Hospital, Paris, 12 Department of Medical Microbiology, Amsterdam UMC, France. 8INSERM UMR 1163 – Institut Imagine, Paris, France. Amsterdam, Netherlands. 13Department of Internal Medicine, 1 9 Imagine Institute, Université de Paris, INSERM UMR 1163, Paris, Hôpital Saint-Louis, Paris, France. 10Sorbonne Paris Nord Univer- Amsterdam UMC, Amsterdam, Netherlands. 14Neurochemical France. *Leader of the Imagine COVID Group. sity, Inserm U1153, Inrae U1125, Cnam, Nutritional Epidemiology Laboratory, Amsterdam UMC, Amsterdam, Netherlands. Research Team (EREN), Bobigny, France. 11In Sitro, San Francisco, 15 Deparment of Intensive Care, Amsterdam UMC, Amsterdam, French COVID Cohort Study Group Laurent Abel1, Claire Andrejak2, CA, USA. *Co-coordinators of The Milieu Intérieur Consortium. Netherlands. 16Department of Clinical Chemistry, Amsterdam UMC, François Angoulvant3, Delphine Bachelet4, Romain Basmaci5, Additional information can be found at: www.milieuinterieur.fr/en. Amsterdam, Netherlands. 17Department of Clinical Epidemiology, Sylvie Behillil6, Marine Beluze7, Dehbia Benkerrou8, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, Krishna Bhavsar4, François Bompart9, Lila Bouadma4, CoV-Contact Cohort Loubna Alavoine1, Karine K. A. Amat2, Netherlands. 18Department of Neurology, Amsterdam UMC, Maude Bouscambert10, Mireille Caralp11, Minerva Cervantes-Gonzalez12, Sylvie Behillil3, Julia Bielicki4, Patricia Bruijning5, Charles Burdet6, Amsterdam, Netherlands. *Leader of the AMC consortium. Anissa Chair4, Alexandra Coelho13, Camille Couffignal4, Eric Caumes7, Charlotte Charpentier8, Bruno Coignard9, Sandrine Couffin-Cadiergues14, Eric D’ortenzio12, Yolande Costa1, Sandrine Couffin-Cadiergues10, Florence Damond8, COVID Human Genetic Effort Laurent Abel1, Alessandro Aiuti2, Charlene Da Silveira4, Marie-Pierre Debray4, Dominique Deplanque15, Aline Dechanet11, Christelle Delmas10, Diane Descamps8, Xavier Duval1, Saleh Al Muhsen3, Fahd Al-Mulla4, Mark S. Anderson5, Diane Descamps16, Mathilde Desvallées17, Alpha Diallo18, Jean-Luc Ecobichon1, Vincent Enouf3, Hélène Espérou10, Andrés Augusto Arias6, Hagit Baris Feldman7, Dusan Bogunovic8, Alphonsine Diouf13, Céline Dorival8, François Dubos19, Wahiba Frezouls1, Nadhira Houhou11, Emila Ilic-Habensus1, Alexandre Bolze9, Anastasiia Bondarenko10, Ahmed A. Bousfiha11, Downloaded from https://www.science.org on February 24, 2022 Xavier Duval4, Philippine Eloy4, Vincent V. E. Enouf20, Hélène Esperou21, Ouifiya Kafif11, John Kikoine11, Quentin Le Hingrat8, Petter Brodin12, Yenan Bryceson12, Carlos D. Bustamante13, Marina Esposito-Farese4, Manuel Etienne22, Nadia Ettalhaoui4, David Lebeaux12, Anne Leclercq1, Jonathan Lehacaut1, Manish Butte14, Giorgio Casari15, Samya Chakravorty16, Nathalie Gault4, Alexandre Gaymard10, Jade Ghosn4, Tristan Gigante23, Sophie Letrou1, Bruno Lina13, Jean-Christophe Lucet14, John Christodoulou17, Elizabeth Cirulli9, Antonio Condino-Neto18, Isabelle Gorenne4, Jérémie Guedj24, Alexandre Hoctin13, Denis Malvy15, Pauline Manchon11, Milica Mandic1, Megan A. Cooper19, Clifton L. Dalgard20, Joseph L. DeRisi21, Isabelle Hoffmann4, Salma Jaafoura21, Ouifiya Kafif4, Mohamed Meghadecha16, Justina Motiejunaite17, Mariama Nouroudine1, Murkesh Desai22, Beth A. Drolet23, Sara Espinosa24, Florentia Kaguelidou25, Sabina Kali4, Antoine Khalil4, Coralie Khan17, Valentine Piquard11, Andreea Postolache11, Caroline Quintin1, Jacques Fellay25, Carlos Flores26, Jose Luis Franco27, Cédric Laouénan4, Samira Laribi4, Minh Le4, Quentin Le Hingrat4, Jade Rexach1, Layidé Roufai10, Zaven Terzian11, Michael Thy18, Peter K. Gregersen28, Filomeen Haerynck29, David Hagin30, Soizic Le Mestre18, Hervé Le Nagard24, François-Xavier Lescure4, Sarah Tubiana1, Sylvie van der Werf3, Valérie Vignali1, Benoit Visseaux8, Rabih Halwani31, Jim Heath32, Sarah E. Henrickson33, Yves Lévy26, Claire Levy-Marchal27, Bruno Lina10, Yazdan Yazdanpanah14 Elena Hsieh34, Kohsuke Imai35, Yuval Itan8, Timokratis Karamitros36, Guillaume Lingas24, Jean Christophe Lucet4, Denis Malvy28, Kai Kisand37, Cheng-Lung Ku38, Yu-Lung Lau39, Yun Ling40, Marina Mambert13, France Mentré4, Noémie Mercier18, 1 Centre d'Investigation Clinique, Inserm CIC 1425, Hôpital Bichat Carrie L. Lucas41, Tom Maniatis42, Davoud Mansouri43, Laszlo Amina Meziane8, Hugo Mouquet20, Jimmy Mullaert4, Claude Bernard, APHP, Paris, France. 2IMEA Fondation Léon M'Ba, Marodi44, Isabelle Meyts45, Joshua D. Milner46, Kristina Mironska47, Nadège Neant24, Marion Noret29, Justine Pages30, Paris, France. 3Institut Pasteur, UMR 3569 CNRS, Université de Trine Mogensen48, Tomohiro Morio49, Lisa F. P. Ng50, Aurélie Papadopoulos21, Christelle Paul18, Nathan Peiffer-Smadja4, Paris, Paris, France. 4University of Basel Children’s Hospital, Basel, Luigi D. Notarangelo51, Giuseppe Novelli52, Antonio Novelli53, Ventzislava Petrov-Sanchez18, Gilles Peytavin4, Olivier Picone31, Switzerland. 5Julius Center for Health Sciences and Primary Care, Cliona O'Farrelly54, Satoshi Okada55, Tayfun Ozcelik56, Oriane Puéchal12, Manuel Rosa-Calatrava10, Bénédicte Rossignol23, University Medical Center Utrecht, Utrecht, Netherlands. Rebeca Perez de Diego57, Anna M. Planas58, Carolina Prando59, Patrick Rossignol32, Carine Roy4, Marion Schneider4, 6 Université de Paris, IAME, Inserm UMR 1137, F-75018, Paris, Aurora Pujol60, Lluis Quintana-Murci61, Laurent Renia62, Caroline Semaille12, Nassima Si Mohammed4, Lysa Tagherset4, France; Hôpital Bichat Claude Bernard, APHP, Paris, France. Alessandra Renieri63, Carlos Rodríguez-Gallego64, Coralie Tardivon4, Marie-Capucine Tellier4, François Téoulé8, 7 Hôpital Pitiè Salpétriere, APHP, Paris, France. 8Université de Paris, Vanessa Sancho-Shimizu65, Vijay Sankaran66, Kelly Schiabor Barrett9, Olivier Terrier10, Jean-François Timsit4, Théo Treoux4, IAME, INSERM UMR 1137, AP-HP, University Hospital Bichat Claude Mohammed Shahrooei67, Andrew Snow68, Pere Soler-Palacín69, Christelle Tual33, Sarah Tubiana4, Sylvie van der Werf34, Bernard, Virology, F-75018 Paris, France. 9Santé Publique France, András N. Spaan70, Stuart Tangye71, Stuart Turvey72, Furkan Uddin73, Noémie Vanel35, Aurélie Veislinger33, Benoit Visseaux16, Saint Maurice, France. 10Pole Recherche Clinique, Inserm, Paris, Mohammed J. Uddin74, Diederik van de Beek75, Sara E. Vazquez76, Aurélie Wiedemann26, Yazdan Yazdanpanah36 France. 11Hôpital Bichat Claude Bernard, APHP, Paris, France. Donald C. Vinh77, Horst von Bernuth78, Nicole Washington9, 12 APHP, Paris, France. 13Virpath Laboratory, International Center of Pawel Zawadzki79, Helen C. Su51*, Jean-Laurent Casanova80* 1 Inserm UMR 1163, Paris, France. 2CHU Amiens, Amiens, France. Research in Infectiology, Lyon University, INSERM U1111, CNRS 3 Hôpital Necker, Paris, France. 4Hôpital Bichat, Paris, France. UMR 5308, ENS, UCBL, Lyon, France . 14IAME Inserm UMR 1138, 1 INSERM U1163, University of Paris, Imagine Institute, Paris, 5 Hôpital Louis Mourrier, Colombes, France. 6Institut Pasteur, Hôpital Bichat Claude Bernard, APHP, Paris, France. 15Service des France. 2San Raffaele Telethon Institute for Gene Therapy, IRCCS Paris, France. 7F-CRIN Partners Platform, AP-HP, Université de Maladies Infectieuses et Tropicales, Groupe Pellegrin, Place Ospedale San Raffaele, Milan, Italy. 3King Saud University, Paris, Paris, France. 8Inserm UMR 1136, Paris, France. 9Drugs Amélie-Raba-Léon, Bordeaux, France. 16Hôpital Hotel Dieu, APHP, Riyadh, Saudi Arabia. 4Dasman Diabetes Institute, Department of for Neglected Diseases Initiative, Geneva, Switzerland. 10Inserm Paris, France. 17Service des explorations fonctionnelles, Hôpital Genetics and Bioinformatics, Dasman, Kuwait. 5University of UMR 1111, Lyon, France. 11Inserm Transfert, Paris, France. Bichat - Claude Bernard, APHP, Paris, France. 18Center for California, San Francisco, San Francisco, CA, USA. 6Universidad de 12 REACTing, Paris, France. 13Inserm UMR 1018, Paris, France. Clinical Investigation, Assistance Publique-Hôpitaux de Paris, Antioquia, Group of Primary Immunodeficiencies, Antioquia, 14 Inserm, Pôle Recherche Clinique, France. 15CIC 1403 Inserm- Bichat-Claude Bernard University Hospital, Paris, France. Colombia. 7The Genetics Institute, Tel Aviv Sourasky Medical CHU Lille, Paris, France. 16Université de Paris, IAME, INSERM Center and Sackler Faculty of Medicine, Tel Aviv University, Tel UMR 1137, AP-HP, University Hospital Bichat Claude Bernard, Amsterdam UMC Covid-19 Biobank Michiel van Agtmael1, Anna Aviv, Israel. 8Icahn School of Medicine at Mount Sinai, New York, Virology, F-75018 Paris, France. 17Inserm UMR 1219, Bordeaux, Geke Algera2, Frank van Baarle2, Diane Bax3, Martijn Beudel4, NY, USA. 9Helix, San Mateo, CA, USA. 10Shupyk National Medical France. 18ANRS, Paris, France. 19CHU Lille, Lille, France. Harm Jan Bogaard5, Marije Bomers1, Lieuwe Bos2, Michela Botta2, Academy for Postgraduate Education, Kiev, Ukraine. 11Clinical 20 Pasteur Institute, Paris, France. 21Inserm sponsor, Paris, Justin de Brabander6, Godelieve Bree6, Matthijs C. Brouwer4, Immunology Unit, Pediatric Infectious Disease Department, Faculty France. 22Rouen - SMIT, France. 23FCRIN INI-CRCT, Nancy, Sanne de Bruin2, Marianna Bugiani7, Esther Bulle2, Osoul Chouchane1, of Medicine and Pharmacy, Averroes University Hospital, LICIA France. 24Inserm UMR 1137, Paris, France. 25Centre d'Investi- Alex Cloherty3, Paul Elbers2, Lucas Fleuren2, Suzanne Geerlings1, Laboratoire d'immunologie clinique, d'inflammation et d'allergie, gation Clinique, Inserm CIC1426, Hôpital Robert Debré, Paris, Bart Geerts8, Theo Geijtenbeek9, Armand Girbes2, Bram Goorhuis1, Hassann Ii University, Casablanca, Morocco. 12Karolinska Institute, France. 26Inserm UMR 955, Créteil, France; Vaccine Research Martin P. Grobusch1, Florianne Hafkamp9, Laura Hagens2, Stockholm, Sweden. 13Stanford University, Stanford, CA, USA. Instiute (VRI), Paris, France. 27F-CRIN INI-CRCT, Paris, France. Jorg Hamann10, Vanessa Harris1, Robert Hemke11, Sabine M. Hermans1, 14 University of California, Los Angeles, CA, USA. 15Medical Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 11 of 12 RES EARCH | R E S E A R C H A R T I C L E Genetics, IRCCS Ospedale San Raffaele, Milan, Italy. 16Department Clinical Center, Fudan University, Shanghai, China. 41Yale School of System, Canary Islands, Spain. 65Imperial College London, London, of Pediatrics and Children’s Healthcare of Atlanta, Emory Medicine, New Haven, CT, USA. 42New York Genome Center, UK. 66Boston Children's Hospital, Harvard Medical School, Boston, University, Atlanta, GA, USA. 17Murdoch Children's Research New York, NY, USA. 43Shahid Beheshti University of Medical Sciences, MA, USA. 67Saeed Pathobiology and Genetic Laboratory, Tehran, Institute, Victoria, Australia. 18University of São Paulo, São Paulo, Tehran, Iran. 44Semmelweis University Budapest, Budapest, Iran. 68Uniformed Services University of the Health Sciences Brazil. 19Washington University School of Medicine, St. Louis, MO, Hungary. 45KU Leuven, Department of Immunology, Microbiology (USUHS), Bethesda, MD, USA. 69Hospital Universitari Vall d'Hebron, USA. 20The American Genome Center; Uniformed Services and Transplantation, Leuven, Belgium. 46Columbia University Barcelona, Spain. 70University Medical Center Utrecht, Amsterdam, University of the Health Sciences, Bethesda, MD, USA. 21University Medical Center, New York, NY, USA. 47University Clinic for Netherlands. 71Garvan Institute of Medical Research, Sydney, of California San Francisco; Chan Zuckerberg Biohub, San Children's Diseases, Skopje, North Macedonia. 48Aarhus University, Australia. 72The University of British Columbia, Vancouver, Canada. Francisco, CA, USA. 22Bai Jerbai Wadia Hospital for Children, Aarhus, Denmark. 49Tokyo Medical & Dental University Hospital, 73 Holy Family Red Crescent Medical College; Centre for Precision Mumbai, India. 23 School of Medicine and Public Health, University Tokyo, Japan. 50Singapore Immunology Network, Singapore. Therapeutics, NeuroGen Children's Healthcare; Genetics and of Wisconsin, Madison, WI, USA. 24Instituto Nacional de Pediatria 51 National Institute of Allergy and Infectious Diseases, National Genomic Medicine Centre, NeuroGen Children's Healthcare, Dhaka, (National Institute of Pediatrics), Mexico City, Mexico. 25Swiss Institutes of Health, Bethesda, MD, USA. 52Department of Bangladesh. 74Mohammed Bin Rashid University of Medicine and Federal Institute of Technology Lausanne, Lausanne, Switzerland. Biomedicine and Prevention, University of Rome “Tor Vergata,” Health Sciences, College of Medicine, Dubai, United Arab Emirates; 26 Research Unit, Hospital Universitario Nuestra Señora de Rome, Italy. 53Bambino Gesù Children's Hospital, Rome, Italy. The Centre for Applied Genomics, Department of Genetics and 54 Candelaria, Canarian Health System, Santa Cruz de Tenerife, Trinity College, Dublin, Ireland. 55Hiroshima University, Hiroshima, Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Spain. 27University of Antioquia, Medellín, Colombia. 28Feinstein Japan. 56Bilkent University, Ankara, Turkey. 57Laboratory of Canada. 75Amsterdam UMC, University of Amsterdam, Institute for Medical Research, Northwell Health USA, Manhasset, Immunogenetics of Human Diseases, Innate Immunity Group, Department of Neurology, Amsterdam Neuroscience, Amsterdam, NY, USA. 29Department of Paediatric Immunology and Pulmonol- IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Netherlands. 76University of California, San Francisco, San ogy, Centre for Primary Immunodeficiency Ghent (CPIG), PID Spain. 58IIBB-CSIC, IDIBAPS, Barcelona, Spain. 59Faculdades Francisco, CA, USA. 77McGill University Health Centre, Montreal, Research Laboratory, Jeffrey Modell Diagnosis and Research Pequeno Príncipe e Instituto de Pesquisa Pelé Pequeno Príncipe, Canada. 78Charité - Berlin University Hospital Center, Berlin, Centre, Ghent University Hospital, Edegem, Belgium. 30The Curitiba, Brazil. 60Neurometabolic Diseases Laboratory, IDIBELL - Germany. 79Molecular Biophysics Division, Faculty of Physics, Genetics Institute Tel Aviv Sourasky Medical Center, Tel Aviv, Hospital Duran I Reynals; Catalan Institution for Research and A. Mickiewicz University, Uniwersytetu Poznanskiego 2, Poznań, Israel. 31Sharjah Institute of Medical Research, College of Medicine, Advanced Studies (ICREA); CIBERER U759, ISCiii Madrid Spain, Poland. 80The Rockefeller University, Howard Hughes Medical University of Sharjah, Sharjah, United Arab Emirates. 32Institute for Barcelona, Spain. 61Institut Pasteur (CNRS UMR2000) and Collège Institute, Necker Hospital, New York, NY, USA. *Leaders of the Systems Biology, Seattle, WA, USA. 33Children's Hospital of de France, Paris, France. 62Infectious Diseases Horizontal Tech- COVID Human Genetic Effort. Philadelphia, Philadelphia, PA, USA. 34Anschutz Medical Campus, nology Center and Singapore Immunology Network, Agency for Aurora, CO, USA. 35Riken, Tokyo, Japan. 36Hellenic Pasteur Science Technology (A*STAR), Singapore. 63Medical Genetics, Institute, Athens, Greece. 37University of Tartu, Tartu, Estonia. University of Siena, Italy; Genetica Medica, Azienda Ospedaliero- 22 June 2020; accepted 16 September 2020 38 Chang Gung University, Taoyuan County, Taiwan. 39The Univer- Universitaria Senese, GEN-COVID Multicenter Study, Italy. 64Hos- Published online 24 September 2020 sity of Hong Kong, Hong Kong, China. 40Shanghai Public Health pital Universitario de Gran Canaria Dr Negrín, Canarian Health 10.1126/science.abd4585 Downloaded from https://www.science.org on February 24, 2022 Bastard et al., Science 370, eabd4585 (2020) 23 October 2020 12 of 12 Autoantibodies against type I IFNs in patients with life-threatening COVID-19 Paul BastardLindsey B. RosenQian ZhangEleftherios MichailidisHans-Heinrich HoffmannYu ZhangKarim DorghamQuentin PhilippotJérémie RosainVivien BéziatJérémy ManryElana ShawLiis HaljasmägiPärt PetersonLazaro LorenzoLucy BizienSophie Trouillet-AssantKerry DobbsAdriana Almeida de JesusAlexandre BelotAnne KallasteEmilie CatherinotYacine Tandjaoui-LambiotteJeremie Le PenGaspard KernerBenedetta BigioYoann SeeleuthnerRui YangAlexandre BolzeAndrás N. SpaanOttavia M. DelmonteMichael S. AbersAlessandro AiutiGiorgio CasariVito LampasonaLorenzo PiemontiFabio CiceriKaya BilguvarRichard P. LiftonMarc VasseDavid M. SmadjaMélanie MigaudJérome HadjadjBenjamin TerrierDarragh DuffyLluis Quintana-MurciDiederik van de BeekLucie RousselDonald C. VinhStuart G. TangyeFilomeen HaerynckDavid DalmauJavier Martinez-PicadoPetter BrodinMichel C. NussenzweigStéphanie Boisson-DupuisCarlos Rodríguez- GallegoGuillaume VogtTrine H. MogensenAndrew J. OlerJingwen GuPeter D. BurbeloJeffrey I. CohenAndrea BiondiLaura Rachele BettiniMariella D'AngioPaolo BonfantiPatrick RossignolJulien MayauxFrédéric Rieux-LaucatEystein S. HusebyeFrancesca FuscoMatilde Valeria UrsiniLuisa ImbertiAlessandra SottiniSimone PagheraEugenia Quiros- RoldanCamillo RossiRiccardo CastagnoliDaniela MontagnaAmelia LicariGian Luigi MarsegliaXavier DuvalJade GhosnJohn S. TsangRaphaela Goldbach-ManskyKai KisandMichail S. LionakisAnne PuelShen-Ying ZhangSteven M. HollandGuy GorochovEmmanuelle JouanguyCharles M. RiceAurélie CobatLuigi D. NotarangeloLaurent AbelHelen C. SuJean- Laurent Casanova, and Andrés Augusto Arias, and Bertrand Boisson, and Soraya Boucherit, and Jacinta Bustamante, and Marwa Chbihi, and Jie Chen, and Maya Chrabieh, and Tatiana Kochetkov, and Tom Le Voyer, and Dana Liu, and Yelena Nemirovskaya, and Masato Ogishi, and Dominick Papandrea, and Cécile Patissier, and Franck Rapaport, and Manon Roynard, and Natasha Vladikine, and Mark Woollett, and Peng Zhang, and Anuj Kashyap, and Li Ding, and Marita Bosticardo, and Qinlu Wang, and Sebastian Ochoa, and Hui Liu, and Samuel D. Chauvin, and Michael Stack, and Galina Koroleva, and Neha Bansal, and Clifton L. Dalgard, and Andrew L. Snow, and Jorge Abad, and Sergio Aguilera-Albesa, and Ozge Metin Akcan, and Ilad Alavi Darazam, and Juan C. Aldave, and Miquel Alfonso Ramos, and Seyed Alireza Nadji, and Gulsum Alkan, and Jerome Allardet-Servent, and Luis M. Allende, and Laia Alsina, and Marie-Alexandra Alyanakian, and Blanca Amador-Borrero, and Zahir Amoura, and Arnau Antolí, and Sevket Arslan, and Sophie Assant, and Terese Auguet, and Axelle Azot, and Fanny Bajolle, and Aurélie Baldolli, and Maite Ballester, and Hagit Baris Feldman, and Benoit Downloaded from https://www.science.org on February 24, 2022 Barrou, and Alexandra Beurton, and Agurtzane Bilbao, and Geraldine Blanchard-Rohner, and Ignacio Blanco, and Adeline Blandinières, and Daniel Blazquez-Gamero, and Marketa Bloomfield, and Mireia Bolivar-Prados, and Raphael Borie, and Ahmed A. Bousfiha, and Claire Bouvattier, and Oksana Boyarchuk, and Maria Rita P. Bueno, and Jacinta Bustamante, and Juan José Cáceres Agra, and Semra Calimli, and Ruggero Capra, and Maria Carrabba, and Carlos Casasnovas, and Marion Caseris, and Martin Castelle, and Francesco Castelli, and Martín Castillo de Vera, and Mateus V. Castro, and Emilie Catherinot, and Martin Chalumeau, and Bruno Charbit, and Matthew P. Cheng, and Père Clavé, and Bonaventura Clotet, and Anna Codina, and Fatih Colkesen, and Fatma Colkesen, and Roger Colobran, and Cloé Comarmond, and Angelo G. Corsico, and David Dalmau, and David Ross Darley, and Nicolas Dauby, and Stéphane Dauger, and Loic de Pontual, and Amin Dehban, and Geoffroy Delplancq, and Alexandre Demoule, and Antonio Di Sabatino, and Jean- Luc Diehl, and Stephanie Dobbelaere, and Sophie Durand, and Waleed Eldars, and Mohamed Elgamal, and Marwa H. Elnagdy, and Melike Emiroglu, and Emine Hafize Erdeniz, and Selma Erol Aytekin, and Romain Euvrard, and Recep Evcen, and Giovanna Fabio, and Laurence Faivre, and Antonin Falck, and Muriel Fartoukh, and Morgane Faure, and Miguel Fernandez Arquero, and Carlos Flores, and Bruno Francois, and Victoria Fumadó, and Francesca Fusco, and Blanca Garcia Solis, and Pascale Gaussem, and Juana Gil-Herrera, and Laurent Gilardin, and Monica Girona Alarcon, and Mónica Girona-Alarcón, and Jean-Christophe Goffard, and Funda Gok, and Rafaela González-Montelongo, and Antoine Guerder, and Yahya Gul, and Sukru Nail Guner, and Marta Gut, and Jérôme Hadjadj, and Filomeen Haerynck, and Rabih Halwani, and Lennart Hammarström, and Nevin Hatipoglu, and Elisa Hernandez-Brito, and María Soledad Holanda-Peña, and Juan Pablo Horcajada, and Sami Hraiech, and Linda Humbert, and Alejandro D. Iglesias, and Antonio Íñigo-Campos, and Matthieu Jamme, and María Jesús Arranz, and Iolanda Jordan, and Fikret Kanat, and Hasan Kapakli, and Iskender Kara, and Adem Karbuz, and Kadriye Kart Yasar, and Sevgi Keles, and Yasemin Kendir Demirkol, and Adam Klocperk, and Zbigniew J. Król, and Paul Kuentz, and Yat Wah M. Kwan, and Jean-Christophe Lagier, and Yu- Lung Lau, and Fleur Le Bourgeois, and Yee-Sin Leo, and Rafael Leon Lopez, and Daniel Leung, and Michael Levin, and Michael Levy, and Romain Lévy, and Zhi Li, and Agnes Linglart, and José M. Lorenzo-Salazar, and Céline Louapre, and Catherine Lubetzki, and Charles-Edouard Luyt, and David C. Lye, and Davood Mansouri, and Majid Marjani, and Jesus Marquez Pereira, and Andrea Martin, and David Martínez Pueyo, and Javier Martinez-Picado, and Iciar Marzana, and Alexis Mathian, and Larissa R. B. Matos, and Gail V. Matthews, and Julien Mayaux, and Jean-Louis Mège, and Isabelle Melki, and Jean-François Meritet, and Ozge Metin, and Isabelle Meyts, and Mehdi Mezidi, and Isabelle Migeotte, and Maude Millereux, and Tristan Mirault, and Clotilde Mircher, and Mehdi Mirsaeidi, and Abián Montesdeoca Melián, and Antonio Morales Martinez, and Pierre Morange, and Clémence Mordacq, and Guillaume Morelle, and Stéphane Mouly, Use of think article is subject to the Terms of service Science (ISSN 1095-9203) is published by the American Association for the Advancement of Science. 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works and Adrián Muñoz-Barrera, and Cyril Nafati, and João Farela Neves, and Lisa F. P. Ng, and Yeray Novoa Medina, and Esmeralda Nuñez Cuadros, and J. Gonzalo Ocejo-Vinyals, and Zerrin Orbak, and Mehdi Oualha, and Tayfun Özçelik, and Qiang Pan Hammarström, and Christophe Parizot, and Tiffany Pascreau, and Estela Paz-Artal, and Rebeca Pérez de Diego, and Aurélien Philippe, and Quentin Philippot, and Laura Planas-Serra, and Dominique Ploin, and Julien Poissy, and Géraldine Poncelet, and Marie Pouletty, and Paul Quentric, and Didier Raoult, and Anne-Sophie Rebillat, and Ismail Reisli, and Pilar Ricart, and Jean-Christophe Richard, and Nadia Rivet, and Jacques G. Rivière, and Gemma Rocamora Blanch, and Carlos Rodrigo, and Carlos Rodriguez-Gallego, and Agustí Rodríguez-Palmero, and Carolina Soledad Romero, and Anya Rothenbuhler, and Flore Rozenberg, and Maria Yolanda Ruiz del Prado, and Joan Sabater Riera, and Oliver Sanchez, and Silvia Sánchez-Ramón, and Agatha Schluter, and Matthieu Schmidt, and Cyril E. Schweitzer, and Francesco Scolari, and Anna Sediva, and Luis M. Seijo, and Damien Sene, and Sevtap Senoglu, and Mikko R. J. Seppänen, and Alex Serra Ilovich, and Mohammad Shahrooei, and David Smadja, and Ali Sobh, and Xavier Solanich Moreno, and Jordi Solé-Violán, and Catherine Soler, and Pere Soler-Palacín, and Yuri Stepanovskiy, and Annabelle Stoclin, and Fabio Taccone, and Yacine Tandjaoui-Lambiotte, and Jean-Luc Taupin, and Simon J. Tavernier, and Benjamin Terrier, and Caroline Thumerelle, and Gabriele Tomasoni, and Julie Toubiana, and Josep Trenado Alvarez, and Sophie Trouillet- Assant, and Jesús Troya, and Alessandra Tucci, and Matilde Valeria Ursini, and Yurdagul Uzunhan, and Pierre Vabres, and Juan Valencia-Ramos, and Ana Maria Van Den Rym, and Isabelle Vandernoot, and Hulya Vatansev, and Valentina Vélez-Santamaria, and Sébastien Viel, and Cédric Vilain, and Marie E. Vilaire, and Audrey Vincent, and Guillaume Voiriot, and Fanny Vuotto, and Alper Yosunkaya, and Barnaby E. Young, and Fatih Yucel, and Faiez Zannad, and Mayana Zatz, and Alexandre Belot, and Giuseppe Foti, and Giacomo Bellani, and Giuseppe Citerio, and Ernesto Contro, and Alberto Pesci, and Maria Grazia Valsecchi, and Marina Cazzaniga, and Christine Bole-Feysot, and Stanislas Lyonnet, and Cécile Masson, and Patrick Nitschke, and Aurore Pouliet, and Yoann Schmitt, and Frederic Tores, and Mohammed Zarhrate, and Laurent Abel, and Claire Andrejak, and François Angoulvant, and Delphine Bachelet, and Romain Basmaci, and Sylvie Behillil, and Marine Beluze, and Dehbia Benkerrou, and Krishna Bhavsar, and François Bompart, and Lila Bouadma, and Maude Bouscambert, and Mireille Caralp, and Minerva Cervantes-Gonzalez, and Anissa Chair, and Alexandra Coelho, and Camille Couffignal, and Sandrine Couffin-Cadiergues, and Eric D’ortenzio, and Charlene Da Silveira, and Marie-Pierre Debray, and Dominique Deplanque, and Diane Descamps, and Mathilde Desvallées, and Alpha Diallo, Downloaded from https://www.science.org on February 24, 2022 and Alphonsine Diouf, and Céline Dorival, and François Dubos, and Xavier Duval, and Philippine Eloy, and Vincent V. E. Enouf, and Hélène Esperou, and Marina Esposito-Farese, and Manuel Etienne, and Nadia Ettalhaoui, and Nathalie Gault, and Alexandre Gaymard, and Jade Ghosn, and Tristan Gigante, and Isabelle Gorenne, and Jérémie Guedj, and Alexandre Hoctin, and Isabelle Hoffmann, and Salma Jaafoura, and Ouifiya Kafif, and Florentia Kaguelidou, and Sabina Kali, and Antoine Khalil, and Coralie Khan, and Cédric Laouénan, and Samira Laribi, and Minh Le, and Quentin Le Hingrat, and Soizic Le Mestre, and Hervé Le Nagard, and François-Xavier Lescure, and Yves Lévy, and Claire Levy-Marchal, and Bruno Lina, and Guillaume Lingas, and Jean Christophe Lucet, and Denis Malvy, and Marina Mambert, and France Mentré, and Noémie Mercier, and Amina Meziane, and Hugo Mouquet, and Jimmy Mullaert, and Nadège Neant, and Marion Noret, and Justine Pages, and Aurélie Papadopoulos, and Christelle Paul, and Nathan Peiffer-Smadja, and Ventzislava Petrov-Sanchez, and Gilles Peytavin, and Olivier Picone, and Oriane Puéchal, and Manuel Rosa-Calatrava, and Bénédicte Rossignol, and Patrick Rossignol, and Carine Roy, and Marion Schneider, and Caroline Semaille, and Nassima Si Mohammed, and Lysa Tagherset, and Coralie Tardivon, and Marie-Capucine Tellier, and François Téoulé, and Olivier Terrier, and Jean-François Timsit, and Théo Treoux, and Christelle Tual, and Sarah Tubiana, and Sylvie van der Werf, and Noémie Vanel, and Aurélie Veislinger, and Benoit Visseaux, and Aurélie Wiedemann, and Yazdan Yazdanpanah, and Laurent Abel, and Andres Alcover, and Hugues Aschard, and Kalla Astrom, and Philippe Bousso, and Pierre Bruhns, and Ana Cumano, and Caroline Demangel, and Ludovic Deriano, and James Di Santo, and Françoise Dromer, and Gérard Eberl, and Jost Enninga, and Jacques Fellay, and Ivo Gomperts-Boneca, and Milena Hasan, and Serge Hercberg, and Olivier Lantz, and Hugo Mouquet, and Etienne Patin, and Sandra Pellegrini, and Stanislas Pol, and Antonio Rausell, and Lars Rogge, and Anavaj Sakuntabhai, and Olivier Schwartz, and Benno Schwikowski, and Spencer Shorte, and Frédéric Tangy, and Antoine Toubert, and Mathilde Touvier, and Marie-Noëlle Ungeheuer, and Matthew L. Albert, and Darragh Duffy, and Lluis Quintana-Murci, and Loubna Alavoine, and Karine K. A. Amat, and Sylvie Behillil, and Julia Bielicki, and Patricia Bruijning, and Charles Burdet, and Eric Caumes, and Charlotte Charpentier, and Bruno Coignard, and Yolande Costa, and Sandrine Couffin-Cadiergues, and Florence Damond, and Aline Dechanet, and Christelle Delmas, and Diane Descamps, and Xavier Duval, and Jean-Luc Ecobichon, and Vincent Enouf, and Hélène Espérou, and Wahiba Frezouls, and Nadhira Houhou, and Emila Ilic-Habensus, and Ouifiya Kafif, and John Kikoine, and Quentin Le Hingrat, and David Lebeaux, and Anne Leclercq, and Jonathan Lehacaut, and Sophie Letrou, and Bruno Lina, and Jean-Christophe Lucet, and Denis Malvy, and Pauline Manchon, and Milica Mandic, and Mohamed Meghadecha, and Justina Motiejunaite, and Mariama Nouroudine, and Valentine Piquard, and Andreea Postolache, and Caroline Quintin, Use of think article is subject to the Terms of service Science (ISSN 1095-9203) is published by the American Association for the Advancement of Science. 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works and Jade Rexach, and Layidé Roufai, and Zaven Terzian, and Michael Thy, and Sarah Tubiana, and Sylvie van der Werf, and Valérie Vignali, and Benoit Visseaux, and Yazdan Yazdanpanah, and Michiel van Agtmael, and Anna Geke Algera, and Frank van Baarle, and Diane Bax, and Martijn Beudel, and Harm Jan Bogaard, and Marije Bomers, and Lieuwe Bos, and Michela Botta, and Justin de Brabander, and Godelieve Bree, and Matthijs C. Brouwer, and Sanne de Bruin, and Marianna Bugiani, and Esther Bulle, and Osoul Chouchane, and Alex Cloherty, and Paul Elbers, and Lucas Fleuren, and Suzanne Geerlings, and Bart Geerts, and Theo Geijtenbeek, and Armand Girbes, and Bram Goorhuis, and Martin P. Grobusch, and Florianne Hafkamp, and Laura Hagens, and Jorg Hamann, and Vanessa Harris, and Robert Hemke, and Sabine M. Hermans, and Leo Heunks, and Markus W. Hollmann, and Janneke Horn, and Joppe W. Hovius, and Menno D. de Jong, and Rutger Koning, and Niels van Mourik, and Jeaninne Nellen, and Frederique Paulus, and Edgar Peters, and Tom van der Poll, and Benedikt Preckel, and Jan M. Prins, and Jorinde Raasveld, and Tom Reijnders, and Michiel Schinkel, and Marcus J. Schultz, and Alex Schuurman, and Kim Sigaloff, and Marry Smit, and Cornelis S. Stijnis, and Willemke Stilma, and Charlotte Teunissen, and Patrick Thoral, and Anissa Tsonas, and Marc van der Valk, and Denise Veelo, and Alexander P. J. Vlaar, and Heder de Vries, and Michèle van Vugt, and W. Joost Wiersinga, and Dorien Wouters, and A. H. (Koos) Zwinderman, and Diederik van de Beek, and Laurent Abel, and Alessandro Aiuti, and Saleh Al Muhsen, and Fahd Al-Mulla, and Mark S. Anderson, and Andrés Augusto Arias, and Hagit Baris Feldman, and Dusan Bogunovic, and Alexandre Bolze, and Anastasiia Bondarenko, and Ahmed A. Bousfiha, and Petter Brodin, and Yenan Bryceson, and Carlos D. Bustamante, and Manish Butte, and Giorgio Casari, and Samya Chakravorty, and John Christodoulou, and Elizabeth Cirulli, and Antonio Condino-Neto, and Megan A. Cooper, and Clifton L. Dalgard, and Joseph L. DeRisi, and Murkesh Desai, and Beth A. Drolet, and Sara Espinosa, and Jacques Fellay, and Carlos Flores, and Jose Luis Franco, and Peter K. Gregersen, and Filomeen Haerynck, and David Hagin, and Rabih Halwani, and Jim Heath, and Sarah E. Henrickson, and Elena Hsieh, and Kohsuke Imai, and Yuval Itan, and Timokratis Karamitros, and Kai Kisand, and Cheng-Lung Ku, and Yu-Lung Lau, and Yun Ling, and Carrie L. Lucas, and Tom Maniatis, and Davoud Mansouri, and Laszlo Marodi, and Isabelle Meyts, and Joshua D. Milner, and Kristina Mironska, and Trine Mogensen, and Tomohiro Morio, and Lisa F. P. Ng, and Luigi D. Notarangelo, and Giuseppe Novelli, and Antonio Novelli, and Cliona O'Farrelly, and Satoshi Okada, and Tayfun Ozcelik, and Rebeca Perez de Diego, and Anna M. Planas, and Carolina Prando, and Aurora Pujol, and Lluis Quintana-Murci, and Laurent Renia, and Alessandra Renieri, and Carlos Rodríguez-Gallego, and Downloaded from https://www.science.org on February 24, 2022 Vanessa Sancho-Shimizu, and Vijay Sankaran, and Kelly Schiabor Barrett, and Mohammed Shahrooei, and Andrew Snow, and Pere Soler-Palacín, and András N. Spaan, and Stuart Tangye, and Stuart Turvey, and Furkan Uddin, and Mohammed J. Uddin, and Diederik van de Beek, and Sara E. Vazquez, and Donald C. Vinh, and Horst von Bernuth, and Nicole Washington, and Pawel Zawadzki, and Helen C. Su, and Jean-Laurent Casanova Science, 370 (6515), eabd4585. • DOI: 10.1126/science.abd4585 The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang used a candidate gene et al. approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard identified individuals with high titers of neutralizing autoantibodies against et al. type I IFN-#2 and IFN-# in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570, p. eabd4585; see also p. 404 Use of think article is subject to the Terms of service Science (ISSN 1095-9203) is published by the American Association for the Advancement of Science. 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works View the article online https://www.science.org/doi/10.1126/science.abd4585 Permissions https://www.science.org/help/reprints-and-permissions Downloaded from https://www.science.org on February 24, 2022 Use of think article is subject to the Terms of service Science (ISSN 1095-9203) is published by the American Association for the Advancement of Science. 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works