RES EARCH ◥ sidered 10 loci mutated in patients with other RESEARCH ARTICLE SUMMARY viral illnesses but directly connected to the three core genes conferring influenza susceptibility: CORONAVIRUS TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG from the TLR3-dependent Inborn errors of type I IFN immunity in patients type I IFN induction pathway, and IFNAR1, IFNAR2, STAT1, and STAT2 from the IRF7- with life-threatening COVID-19 and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes Qian Zhang et al. of inheritance at these 13 loci. INTRODUCTION: Clinical outcomes of human the general hypothesis that life-threatening RESULTS: We found an enrichment in variants severe acute respiratory syndrome corona- COVID-19 in some or most patients may be predicted to be loss-of-function (pLOF), with a virus 2 (SARS-CoV-2) infection range from caused by monogenic inborn errors of immu- minor allele frequency <0.001, at the 13 can- silent infection to lethal coronavirus disease nity to SARS-CoV-2 with incomplete or com- didate loci in the 659 patients with life- 2019 (COVID-19). Epidemiological studies have plete penetrance. We sequenced the exome or threatening COVID-19 pneumonia relative to identified three risk factors for severe disease: genome of 659 patients of various ancestries the 534 subjects with asymptomatic or benign being male, being elderly, and having other with life-threatening COVID-19 pneumonia infection (P = 0.01). Experimental tests for all medical conditions. However, interindividual and 534 subjects with asymptomatic or benign 118 rare nonsynonymous variants (including clinical variability remains huge in each demo- infection. We tested the specific hypothesis that both pLOF and other variants) of these 13 genes graphic category. Discovering the root cause inborn errors of Toll-like receptor 3 (TLR3)– found in patients with critical disease identified and detailed molecular, cellular, and tissue- and and interferon regulatory factor 7 (IRF7)– 23 patients (3.5%), aged 17 to 77 years, carrying body-level mechanisms underlying life-threatening dependent type I interferon (IFN) immunity 24 deleterious variants of eight genes. These COVID-19 is of the utmost biological and medical that underlie life-threatening influenza pneu- variants underlie autosomal-recessive (AR) defi- importance. monia also underlie life-threatening COVID-19 ciencies (IRF7 and IFNAR1) and autosomal- pneumonia. We considered three loci identified dominant (AD) deficiencies (TLR3, UNC93B1, RATIONALE: We established the COVID Human as mutated in patients with life-threatening TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2) Genetic Effort (www.covidhge.com) to test influenza: TLR3, IRF7, and IRF9. We also con- in four and 19 patients, respectively. These patients had never been hospitalized for other SARS-COV-2 life-threatening viral illness. Plasmacytoid den- dritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and Downloaded from https://www.science.org on March 04, 2022 TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibro- Asymptomatic/mild Life-threatening blasts were susceptible to SARS-CoV-2 infec- tion in vitro. IFNAR1 CONCLUSION: At least 3.5% of patients with life- threatening COVID-19 pneumonia had known IRF7 (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 TLR3 deficiencies) genetic defects at eight of the Inborn errors of type I IFN immunity 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential IRF7 Type I IFNs roles for both the double-stranded RNA sensor Plasmacytoid TLR3 and type I IFN cell-intrinsic immunity in dendritic cells the control of SARS-CoV-2 infection. Type I IFN IFNAR2 IFNAR1 administration may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection. ▪ TLR3 STAT1 STAT2 UNC93B1 IRF7 IRF9 The full author list and the list of affiliations is available in TRAF3 TRIF the full article online. TBK1 Corresponding author: Jean-Laurent Casanova (casanova@ NEMO rockefeller.edu) IRF3 Type I IFNs ISGs This is an open-access article distributed under the terms Respiratory epithelial cells of the Creative Commons Attribution license (https:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Inborn errors of TLR3- and IRF7-dependent type I IFN production and amplification underlie life- Cite this article as Q. Zhang et al., Science 370, eabd4570 threatening COVID-19 pneumonia. Molecules in red are encoded by core genes, deleterious variants of (2020). DOI: 10.1126/science.abd4570 which underlie critical influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Molecules represented in bold READ THE FULL ARTICLE AT are encoded by genes with variants that also underlie critical COVID-19 pneumonia. https://doi.org/10.1126/science.abd4570 Zhang et al., Science 370, 422 (2020) 23 October 2020 1 of 1 RES EARCH ◥ caused by monogenic inborn errors of immu- RESEARCH ARTICLE nity to SARS-CoV-2 with incomplete or com- plete penetrance (4). We enrolled 659 patients CORONAVIRUS (74.5% men and 25.5% women, 13.9% of whom Inborn errors of type I IFN immunity in patients with died) of various ancestries between 1 month and 99 years of age (Fig. 1A). These patients life-threatening COVID-19 were hospitalized for life-threatening pneumo- nia caused by SARS-CoV-2 (critical COVID-19). We sequenced their whole genome (N = 364) Qian Zhang1, Paul Bastard2,3*, Zhiyong Liu1*, Jérémie Le Pen4*, Marcela Moncada-Velez1*, Jie Chen1*, or exome (N = 295), and principal component Masato Ogishi1*, Ira K. D. Sabli5*, Stephanie Hodeib5*, Cecilia Korol2*, Jérémie Rosain2,3*, analysis (PCA) on these data confirmed their Kaya Bilguvar6*, Junqiang Ye7*, Alexandre Bolze8*, Benedetta Bigio1*, Rui Yang1*, ancestries (Fig. 1B). Andrés Augusto Arias1,9,10*, Qinhua Zhou1*, Yu Zhang11,12*, Fanny Onodi13, Sarantis Korniotis13, Léa Karpf13, Quentin Philippot2,3, Marwa Chbihi2,3, Lucie Bonnet-Madin14, Karim Dorgham15, Candidate variants at 13 human loci that Nikaïa Smith16, William M. Schneider4, Brandon S. Razooky4, Hans-Heinrich Hoffmann4, govern immunity to influenza virus Eleftherios Michailidis4, Leen Moens17, Ji Eun Han1, Lazaro Lorenzo2,3, Lucy Bizien2,3, Philip Meade18, We first tested the specific hypothesis that in- Anna-Lena Neehus2,3, Aileen Camille Ugurbil1, Aurélien Corneau19, Gaspard Kerner2,3, Peng Zhang1, born errors of Toll-like receptor 3 (TLR3)– and Franck Rapaport1, Yoann Seeleuthner2,3, Jeremy Manry2,3, Cecile Masson20, Yohann Schmitt20, interferon regulatory factor 7 (IRF7)–dependent Agatha Schlüter21, Tom Le Voyer2,3, Taushif Khan22, Juan Li1, Jacques Fellay23,24,25, Lucie Roussel26, type I interferon (IFN) immunity, which un- Mohammad Shahrooei27,28, Mohammed F. Alosaimi29, Davood Mansouri30,31,32, Haya Al-Saud33, derlie life-threatening influenza pneumonia, Fahd Al-Mulla34, Feras Almourfi33, Saleh Zaid Al-Muhsen35, Fahad Alsohime29, Saeed Al Turki36,37, may also underlie life-threatening COVID-19 Rana Hasanato29, Diederik van de Beek38, Andrea Biondi39, Laura Rachele Bettini39, pneumonia (5) (Fig. 2). We considered three Mariella D’Angio’39, Paolo Bonfanti40, Luisa Imberti41, Alessandra Sottini41, Simone Paghera41, loci previously shown to be mutated in patients Eugenia Quiros-Roldan42, Camillo Rossi43, Andrew J. Oler44, Miranda F. Tompkins45, Camille Alba45, with critical influenza pneumonia: TLR3 (6), Isabelle Vandernoot46, Jean-Christophe Goffard47, Guillaume Smits46, Isabelle Migeotte48, IRF7 (7), and IRF9 (8). We also considered Filomeen Haerynck49, Pere Soler-Palacin50, Andrea Martin-Nalda50, Roger Colobran51, 10 loci mutated in patients with other viral Pierre-Emmanuel Morange52, Sevgi Keles53, Fatma Çölkesen54, Tayfun Ozcelik55, illnesses but directly connected to the three Kadriye Kart Yasar56, Sevtap Senoglu56, Şemsi Nur Karabela56, Carlos Rodríguez-Gallego57,58, core genes conferring influenza susceptibility: Giuseppe Novelli59, Sami Hraiech60, Yacine Tandjaoui-Lambiotte61,62, Xavier Duval63,64, TICAM1/TRIF (9), UNC93B1 (10), TRAF3 (11), Cédric Laouénan63,64,65, COVID-STORM Clinicians†, COVID Clinicians†, Imagine COVID Group†, TBK1 (12), IRF3 (13), and NEMO/IKBKG (14) in French COVID Cohort Study Group†, CoV-Contact Cohort†, Amsterdam UMC Covid-19 Biobank†, the TLR3-dependent type I IFN induction path- COVID Human Genetic Effort†, NIAID-USUHS/TAGC COVID Immunity Group†, Andrew L. Snow66, way, and IFNAR1 (15), IFNAR2 (16), STAT1 Downloaded from https://www.science.org on March 04, 2022 Clifton L. Dalgard45,67, Joshua D. Milner68, Donald C. Vinh26, Trine H. Mogensen69,70, Nico Marr22,71, (17), and STAT2 (18) in the IRF7- and IRF9- András N. Spaan1,72, Bertrand Boisson1,2,3, Stéphanie Boisson-Dupuis1,2,3, Jacinta Bustamante1,2,3,73, dependent type I IFN amplification pathway. Anne Puel1,2,3, Michael J. Ciancanelli1,74, Isabelle Meyts17,75, Tom Maniatis7,76, Vassili Soumelis13,77, We collected both monoallelic and biallelic Ali Amara14, Michel Nussenzweig78,79, Adolfo García-Sastre18,80,81,82, Florian Krammer18, nonsynonymous variants with a minor allele Aurora Pujol21, Darragh Duffy16, Richard P. Lifton83,84,85‡, Shen-Ying Zhang1,2,3‡, Guy Gorochov15‡, frequency (MAF) <0.001 at all 13 loci. Twelve Vivien Béziat1,2,3‡, Emmanuelle Jouanguy1,2,3‡, Vanessa Sancho-Shimizu5‡, Charles M. Rice4‡, of the 13 candidate loci are autosomal, whereas Laurent Abel1,2,3‡, Luigi D. Notarangelo11,12§, Aurélie Cobat1,2,3§, NEMO is X-linked. For the latter gene, we con- Helen C. Su11,12§, Jean-Laurent Casanova1,2,3,79,86§¶ sidered only a recessive model (19). Autosomal- dominant (AD) inheritance has not been proven Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for six of the 12 autosomal loci (UNC93B1, IRF7, ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment IFNAR1, IFNAR2, STAT2, and IRF9). Never- in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like theless, we considered heterozygous variants receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity because none of the patients enrolled had to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects been hospitalized for critical viral infections with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we before COVID-19, raising the possibility that experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies any underlying genetic defects that they might in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting have display a lower penetrance for influenza this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN and other viral illnesses than for COVID-19, immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection. which is triggered by a more virulent virus. Enrichment of variants predicted to be LOF S evere acute respiratory syndrome coro- and (iii) having various underlying medical at the influenza susceptibility loci navirus 2 (SARS-CoV-2) has already conditions (1). However, even taking these We found four unrelated patients with bial- claimed at least 1 million lives, has been factors into account, there is immense inter- lelic variants of IRF7 or IFNAR1 (Table 1 and detected in at least 20 million people, individual clinical variability in each demo- table S1). We also found 113 patients carrying and has probably infected at least anoth- graphic category considered. Following on 113 monoallelic variants at 12 loci: TLR3 (N = 7 er 200 million. The clinical manifestations from our human genetic studies of other patients/7 variants), UNC93B1 (N = 10/9), range from silent infection to lethal disease, severe infectious diseases (2, 3), we established TICAM1 (N = 17/15), TRAF3 (N = 6/6), TBK1 with an infection fatality rate of 0.1 to 0.9%. the COVID Human Genetic Effort (https:// (N = 12/11), IRF3 (N = 5/5), IRF7 (N = 20/13), Three epidemiological factors increase the www.covidhge.com) to test the general hy- IFNAR1 (N = 14/13), IFNAR2 (N = 17/15), STAT1 risk of severity: (i) increasing age, decade by pothesis that in some patients, life-threatening (N = 4/4), STAT2 (N = 11/11), and IRF9 (N = decade, after the age of 50, (ii) being male, coronavirus disease 2019 (COVID-19) may be 4/4). We detected no copy number variation Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 1 of 13 RES EARCH | R E S E A R C H A R T I C L E A B 1000 genomes Men Asymptomatic/mild COVID Women Life -threatening COVID without LOF variants Life -threatening COVID with LOF variants 0.01 Age and sex distribution Asymptomatic/mild Life-threatening 250 0.00 Number of individuals 200 -0.01 PC2 150 100 -0.02 50 0 -0.03 10 0 0 10 0 0 20 9 30 9 40 9 50 9 60 9 9 20 9 30 9 40 9 50 9 60 9 9 <1 >7 <1 >7 -1 -2 -3 -4 -5 -6 -1 -2 -3 -4 -5 -6 Age (years) -0.01 0.00 0.01 0.02 0.03 PC1 Fig. 1. Demographic and genetic data for the COVID-19 cohort. (A) Age and sex distribution of patients with life-threatening COVID-19. (B) PCA of patient (with or without LOF variants in the 13 candidate genes) and control cohorts (patients with mild or asymptomatic disease and individuals from the 1000 Genomes Project). 1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. 3University of Paris, Imagine Institute, Paris, France. 4Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. 5Department of Paediatric Infectious Diseases & Virology, Imperial College London, London, UK. 6Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA. 7Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA. 8Helix, San Mateo, CA, USA. 9Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia. 10 School of Microbiology, University of Antioquia UdeA, Medellin, Colombia. 11Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA. 12NIAID Clinical Genomics Program, NIH, Bethesda, MD, USA. 13Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, Paris, France. 14Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR 7212, Université de Paris, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France. 15Sorbonne Université, Inserm, Centre d’Immunologie et des Maladies Infectieuses–Paris (CIMI PARIS), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Pitié-Salpêtrière, Paris, France. 16Translational Immunology Lab, Institut Pasteur, Paris, France. 17Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 18Department of Microbiology, Icahn Downloaded from https://www.science.org on March 04, 2022 School of Medicine at Mount Sinai, New York, NY, USA. 19Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France. 20Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France. 21Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. 22Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar. 23School of Life sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 24Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 25Swiss Institue of Bioinformatics, Lausanne, Switzerland. 26 Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada. 27Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran. 28Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium. 29Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 30Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 31The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of, Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti, University of Medical Sciences, Tehran, Iran. 32Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti, Iran. 33National Center of Genomics Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. 34Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Kuwait. 35Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia. 36Translational Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Misery of National Guard Health Affairs, Riyadh, Saudi Arabia. 37Cancer & Blood Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 38 Amsterdam UMC, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands. 39Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy. 40Department of Infectious Diseases, San Gerardo Hospital–University of Milano-Bicocca, Monza, Italy. 41CREA Laboratory, Diagnostic Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy. 42Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy. 43Chief Medical Officer, ASST Spedali Civili di Brescia, Brescia, Italy. 44Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA. 45 PRIMER, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 46Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 47Department of Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 48Fonds de la Recherche Scientifique (FNRS) and Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 49Department of Paediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Lab, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium. 50Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain. 51Immunology Division, Genetics Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain. 52Aix Marseille Univ, INSERM, INRAE, C2VN, CHU Timone, Marseille, France. 53Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey. 54Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey. 55Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey. 56Departments of Infectious Diseases and Clinical Microbiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey. 57Department of Immunology, Hospital Universitario de G.C. Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain. 58University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain. 59Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Rome, Italy. 60Intensive Care Unit, AP-HM, Marseille, France. 61Avicenne Hospital Intensive Care Unit, APHP, Bobigny, INSERM U1272 Hypoxia & Lung, Paris, France. 62PH Réanimation CHU Avicenne, Bobigny, INSERM U1272 Hypoxie & Poumon, Paris, France. 63Université de Paris, IAME UMR-S 1137, INSERM, Paris, France. 64Inserm CIC 1425, Paris, France. 65AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France. 66Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 67Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 68Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University, New York, USA. 69Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark. 70 Department of Biomedicine, Aarhus University, Aarhus, Denmark. 71College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar. 72Department of Medical Microbiology, Utrecht UMC, Utrecht, Netherlands. 73Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France. 74Turnstone Biologics, New York, NY, USA. 75Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 76New York Genome Center, New York, NY, USA. 77AP-HP, Hôpital Saint-Louis, Laboratoire d’Immunologie, Paris, France. 78Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA. 79Howard Hughes Medical Institute, New York, NY, USA. 80Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 81Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 82The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 83Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA. 84Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. 85Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA. 86Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France. *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. ¶Corresponding author. Email: casanova@rockefeller.edu Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 2 of 13 RES EARCH | R E S E A R C H A R T I C L E for these 13 genes. Unexpectedly, one of these (IFNAR1 p.Pro335del) (21). Nine of the 118 or mild SARS-CoV-2 infection, we found only variants has been reported in patients with biallelic or monoallelic variants were predicted one heterozygous pLOF variation with a MAF life-threatening influenza pneumonia (TLR3 to be LOF (pLOF), whereas the remaining 109 <0.001 at the 13 loci (IRF7 p.Leu99fs). A PCA- p.Pro554Ser) (6, 20) and another was shown were missense or in-frame indels (table S1). In adjusted burden test on the 12 autosomal to be both deleterious and dominant-negative a sample of 534 controls with asymptomatic loci revealed significant enrichment in pLOF variants in patients relative to controls [P = 0.01; odds ratio (OR) = 8.28; 95% confidence Plasmacytoid dendritic cells interval (CI) = 1.04 to 65.64] under an AD mode of inheritance. The same analysis performed IRF7 type I IFNs on synonymous variants with a MAF <0.001 was not significant (P = 0.19), indicating that our ethnicity-adjusted burden test was well calibrated. IFNAR1 IFNAR2 Experimentally deleterious alleles at the influenza susceptibility loci in 3.5% of patients We tested these 118 variants experimentally in ad hoc overexpression systems. We found that TLR3 STAT1 STAT2 24 variants of eight genes were deleterious IRF7 IRF9 (including all the pLOF variants) because they UNC93B1 TRAF3 were loss-of-expression, LOF, or severely hypo- TRIF TBK1 morphic: TLR3 (N = 4 variants), UNC93B1 NEMO (N = 1), TICAM1 (N = 3), TBK1 (N = 2), IRF3 (N = 2), IRF7 (N = 8), IFNAR1 (N = 3), and IRF3 Type I IFNs ISGs IFNAR2 (N = 1) (table S1, Fig. 3, and figs. S1 to S8). Consistently, heterozygous LOF variants of IRF3 and IRF7 were reported in single pa- tients with life-threatening influenza pneumo- Respiratory epithelial cells nia (22, 23). The remaining 94 variants were Fig. 2. Illustration of TLR3- and IRF7-dependent type I IFN production and amplification circuit. biochemically neutral. Twenty-three patients Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza carried these 24 deleterious variants, resulting Downloaded from https://www.science.org on March 04, 2022 pneumonia with incomplete penetrance; deleterious variants of genes encoding biochemically related molecules in in four autosomal-recessive (AR) deficiencies blue underlie other viral illnesses. Type I IFNs also induce themselves. ISGs, interferon-stimulated genes. (homozygosity or compound heterozygosity Table 1. Disease-causing variants identified in patients with life-threatening COVID-19. Gene Inheritance Genetic form Genotype Gender Age [years] Ancestry/residence Outcome TLR3 AD Known p.Ser339fs/WT M 40 Spain Survived ............................................................................................................................................................................................................................................................................................................................................ TLR3 AD Known p.Pro554Ser/WT M 68 Italy Survived ............................................................................................................................................................................................................................................................................................................................................ TLR3 AD Known p.Trp769*/WT M 77 Italy Survived ............................................................................................................................................................................................................................................................................................................................................ TLR3 AD Known p.Met870Val/WT M 56 Colombia/Spain Survived ............................................................................................................................................................................................................................................................................................................................................ UNC93B1 AD New p.Glu96*/WT M 48 Venezuela/Spain Survived ............................................................................................................................................................................................................................................................................................................................................ TICAM1 AD Known p.Thr4Ile/WT M 49 Italy Survived ............................................................................................................................................................................................................................................................................................................................................ TICAM1 AD Known p.Ser60Cys/WT F 61 Vietnam/France Survived ............................................................................................................................................................................................................................................................................................................................................ TICAM1 AD Known p.Gln392Lys/WT F 71 Italy Deceased ............................................................................................................................................................................................................................................................................................................................................ TBK1 AD Known p.Phe24Ser/WT F 46 Venezuela/Spain Survived ............................................................................................................................................................................................................................................................................................................................................ TBK1 AD Known p.Arg308*/WT M 17 Turkey Survived ............................................................................................................................................................................................................................................................................................................................................ IRF3 AD Known p.Glu49del/WT F 23 Bolivia/Spain Survived ............................................................................................................................................................................................................................................................................................................................................ IRF3 AD Known p.Asn146Lys/WT F 60 Italy Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AR Known p.Pro364fs/p.Pro364fs F 49 Italy/Belgium Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AR Known p.Met371Val/p.Asp117Asn M 50 Turkey Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AD New p.Arg7fs/WT M 60 Italy Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AD New p.Gln185*/WT M 44 France Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AD New p.Pro246fs/WT M 41 Spain Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AD New p.Arg369Gln/WT M 69 Italy Survived ............................................................................................................................................................................................................................................................................................................................................ IRF7 AD New p.Phe95Ser/WT M 37 Turkey Survived ............................................................................................................................................................................................................................................................................................................................................ IFNAR1 AR Known p.Trp73Cys/Trp73Cys M 38 Turkey Survived ............................................................................................................................................................................................................................................................................................................................................ IFNAR1 AR Known p.Ser422Arg/Ser422Arg M 26 Pakistan/Saudi Arabia Deceased ............................................................................................................................................................................................................................................................................................................................................ IFNAR1 AD New p.Pro335del/WT F 23 China/Italy Survived ............................................................................................................................................................................................................................................................................................................................................ IFNAR2 AD New p.Glu140fs/WT F 54 Belgium Survived ............................................................................................................................................................................................................................................................................................................................................ Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 3 of 13 RES EARCH | R E S E A R C H A R T I C L E A TLR3 B TICAM1 C TBK1 4 4 2 IFNB reporter (fold change) IFNB reporter (fold change) IFNL mRNA (fold change) 3 3 2 2 1 * ** * * * * 1 1 * * * * 0 0 * 0 * R308* V152L G159A EV S186L F24S WT R384Q N388S E653Q P659S I397T L508I A535T I522M NT LT M595L A111T Q392K Q702R R141X V302L R251G F732L V80M EV T157M D557N WT S465N G598W L386P S134P T4I S339fs R71Q NT WT P554S T377I W769* R867Q EV S60C E746* M870V D IRF3 Untreated E Untreated IRF7 10 Sendai virus 6 IFNB reporter (fold change) IFNB reporter (fold change) Sendai virus 8 4 6 4 * * * * 2 * 2 * * * ** * * * 0 0 N146K EV E49del G145_E200del Q421* WT G337R R227Q R285Q R423P P364fs L401V F410V D117N G133R Q185* T254A R369Q M371V A419T P246fs G214E F95S R37H WT R7fs EV F 1.5 G 1.5 Downloaded from https://www.science.org on March 04, 2022 IFNAR1 IFN-α2 IFNAR2 IFN-α2 p-STAT1 (fold change) p-STAT1 (fold change) IFN-γ IFN-γ 1.0 1.0 0.5 0.5 0.0 0.0 E386L E386L NT A424T NT WT A424T P385L S450L P295L P385L S450L G57R Q80H T83A R306C E515K G57R Q80H T83A R306C E515K V307I V307I V225fs V225fs I169M I169M I183V I183V A24V A24V S215G S215G E37Q E37Q WT WT I197T NT P295L S422R S422R H283R T318C S324N H283R T318C S324N W73C W73C P335del P335del E140fs E140fs EV N88S EV E138V P346S P362S N88S EV E138V P346S P362S M73V M73V E138_F139insS I197T NT WT EV E138_F139insS Fig. 3. Impact of TLR3, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2 luciferase reporter and a constitutively expressed reporter. Cells were either variants on type I IFN signaling. (A) TLR3-deficient P2.1 fibrosarcoma cells left untreated or infected with Sendai virus for 24 hours before the normalized were stably transfected with plasmids expressing WT or mutant forms of TLR3, measurement of luciferase activity. The differences between variants and WT were and IFNL1 mRNA levels were determined by reverse transcription quantitative evaluated using two-way ANOVA (*P < 0.05). (E) HEK293T cells were transiently PCR. IFNL1 mRNA levels were expressed relative to the housekeeping gene GUS transfected with WT and mutant forms of IRF7, together with an IFN-b luciferase and then normalized. IFNL1 was undetectable in unstimulated cells. The differences reporter and a constitutively expressed reporter. Cells were either left untreated between variants and WT were tested using one-way ANOVA (*P < 0.05). (B) TICAM1- or infected with Sendai virus for 24 hours before the normalized measurement of deficient SV40-Fib cells were transiently transfected with WT or mutant forms of luciferase activity. The differences between variants and WT were tested using TICAM1, together with an IFN-b luciferase reporter and a constitutively expressed two-way ANOVA (*P < 0.05). (F and G) IFNAR1- or IFNAR2-deficient SV40-Fib cells reporter. Normalized luciferase induction was measured 24 hours after were transiently transfected with WT or mutant forms of IFNAR1 for 36 hours, transfection. The differences between variants and WT were tested using one-way and either left untreated or stimulated with IFN-a2 or IFN-g. Fluorescence-activated ANOVA (*P < 0.05). (C) HEK293T cells were transiently transfected with WT cell sorting (FACS) staining with anti-p-STAT1 antibody and the z-score of the MFI and mutant forms of TBK1, together with an IFN-b luciferase reporter and a were assessed. Asterisks indicate variants with MFI <50% of WT. Variants in red were constitutively expressed reporter. Normalized luciferase activity was measured identified in COVID-19 patients. Variants in blue are known deleterious variants and 24 hours after transfection. The differences between variants and WT were tested served as negative controls. EV, empty vector; LT, lipofectamine. Three technical using one-way ANOVA (*P < 0.05). (D) IRF3-deficient HEK293T cells were repeats were performed for (A) to (E). Means and SD are shown in the columns and transiently transfected with WT and mutant forms of IRF3, together with an IFN-b horizontal bars when appropriate. Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 4 of 13 RES EARCH | R E S E A R C H A R T I C L E A PHA-T cells C1 C2 P1 P2 C3 C4 P3 WT/WT WT/WT P364fs/P364fs Q185*/WT WT/WT WT/WT M371V/D117N IFN- 2 - + - + - + - + - + - + - + IRF7 MX1 GAPDH B pDC 10 10 IAV SARS-CoV-2 Type I IFNs Type III IFNs P1 P364fs/P364fs 5 5 (fold change) 0 0 -5 -5 -10 -10 -10 -5 0 5 10 15 -10 -5 0 5 10 15 C1 WT/WT (fold change) C1 WT/WT (fold change) C pDC 25 4000 C: IRF7 WT/WT Downloaded from https://www.science.org on March 04, 2022 20 P1: IRF7 P364fs/P364fs 2 (ng/ml) 1 (pg/ml) ,-;+7'<=>?&0@ 3000 ,-:39';<=>&0? 15 2000 10 IFN- IFN- 1000 5 ND ND ND ND ND ND ND 0 6 C P1 C P1 C P1 C P1 C P1 C P1 -.1 -.1 *+ *+ .1 -.1 + + -. . *+ ',* + ',* ,*- '() ,*- ()* '() ()* Medium IAV ',* SARS-CoV-2 Medium IAV ',* SARS-CoV-2 ()* % '() % % 5' % &' 5' & 5' 45 &' /0 & /0 34 /0 34 /0 $% $% 34 % 23 % Fig. 4. Type I IFN responses in patient cells defective for IRF7. (A) Levels infected with influenza A virus (IAV) or SARS-CoV-2, and RNA-seq was performed. of the IRF7 protein in PHA-T cells from two patients with AR IRF7 deficiency Genes with expression >2.5-fold higher or lower in C1 after infection are plotted (P1 and P3), one patient with AD IRF7 deficiency (P2), and four healthy donors as the fold change in expression. Red dots are type I IFN genes; blue dots are type III (C1 to C4). Cells were either left untreated or stimulated with IFN-a2 for IFN genes. (C) pDCs isolated from healthy donor C and IRF7-deficient patient 24 hours, and protein levels were measured by Western blotting. MX1 was used (P1) were either left untreated (Medium) or infected with IAV or SARS-CoV-2, as a positive control for IFN-a2 treatment. (B) pDCs isolated from an AR IRF7- and the production of IFN-a2 and IFN-l1 was measured by CBA and ELISA, deficient patient (P1) and a healthy donor (C1) were either left untreated or respectively, on the supernatant. ND, not detected. for IRF7; homozygosity for IFNAR1) and 19 AD Impaired TLR3- and IRF7-dependent type I array (CBA), enzyme-linked immunosorbent deficiencies. These 23 patients did not carry immunity in patient cells in vitro assay (ELISA), and RNA sequencing (RNA- candidate variants at the other 417 loci known to We tested cells from patients with selected seq) (Fig. 4, B and C). We also showed that underlie inborn errors of immunity (table S2) genotypes and showed that PHA-driven T cell PHA-T cells from a patient with AR IFN-a/b (24–26). These findings suggest that at least blasts (PHA-T cells) from patients with AR receptor 1 (IFNAR1) deficiency had impaired 23 (3.5%) unrelated patients of the 659 patients or AD IRF7 deficiency had low levels of IRF7 IFNAR1 expression and responses to IFN-a2 or tested suffered from a deficiency at one of eight expression (Fig. 4A). We then isolated circulat- IFN-b, and that the patient’s SV40-transformed loci among the 13 tested: four patients with a ing plasmacytoid dendritic cells (pDCs) from fibroblast (SV40-Fib) cells did not respond to known AR disorder (IRF7 or IFNAR1) (7, 15), a patient with AR IRF7 deficiency (fig. S9A) IFN-a2 or IFN-b (Fig. 5). We then infected 11 with a known AD disorder (TLR3, TICAM1, (7). These cells were present in normal pro- TLR3−/−, TLR3+/−, IRF7−/− SV40-Fib cells, and TBK1, or IRF3) (6, 9, 12, 13, 20), and eight with portions (fig. S9B), but they did not produce IRF7−/− SV40-Fib cells rescued with wild-type a previously unknown AD genetic disorder any detectable type I or III IFNs in response to (WT) IRF7; IFNAR1−/− SV40-Fib cells, and (UNC93B1, IRF7, IFNAR1, or IFNAR2). SARS-CoV-2, as analyzed by cytometric bead IFNAR1−/− SV40-Fib cells rescued with WT Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 5 of 13 RES EARCH | R E S E A R C H A R T I C L E A PHA-T cells isotype mAb 100 C1 C2 P5 anti -IFNAR1 mAb 80 % of Max 60 C1, C2: IFNAR1 WT/WT 40 P5: IFNAR1 W73C/W73C 20 0 101 102 103 101 102 103 101 102 103 IFNAR1 B PHA-T cells SV40-Fib cells Unstimulated IFN- 2 IFN- IL-27 IFN- 2 IFN- IFN- Stimulated 0 100 100 0 80 80 0 60 60 C3 0 40 40 WT/WT % of Max 0 20 20 0 0 100 100 80 80 60 60 P5 40 40 W73C/W73C 20 20 0 0 102 103 104 102 103 104 102 103 104 101 102 103 101 102 103 101 102 103 p-STAT1 Fig. 5. Type I IFN responses in patient cells defective for IFNAR1. (A) FACS staining of IFNAR1 on the surface of PHA-T cells from a patient with AR IFNAR1 deficiency (P5) and healthy donors (C1 and C2). (B) PHA-T cells and SV40-Fib from a patient with AR IFNAR1 deficiency (P5) and a healthy donor (C3) were stimulated with IFN-a2 or IFN-b, and p-STAT1 levels were determined by FACS. Interleukin-27 stimulation served as a positive control on PHA-T cells, whereas IFN-g stimulation served as a positive control on SV40-Fib cells. Downloaded from https://www.science.org on March 04, 2022 IFNAR1, all of which were previously trans- (Fig. 7). By contrast, previously published co- control of SARS-CoV-2 infection in the lungs, duced with angiotensin-converting enzyme 2 horts of patients hospitalized with unexplained, consistent with their previously documented (ACE2) and transmembrane protease, serine 2 severe COVID-19 had various serum IFN-a roles in pulmonary immunity to influenza (TMPRSS2). SARS-CoV-2 infection levels were levels, significantly higher than our 10 patients virus (5–8). These genotypes were silent until higher in mutant cells than in cells from healthy [one-way analysis of variance (ANOVA), P = infection with SARS-CoV-2. The most thought- donors, and transduction of WT IRF7 or IFNAR1 1.4 × 10−7; Fig. 7] (27, 28). Another 29 patients provoking examples are the AR deficiencies rescued their defects (Fig. 6). Collectively, these from our cohort displaying auto-antibodies of IRF7 and IFNAR1. AR IRF7 deficiency was findings showed that AR IRF7 deficiency im- (auto-Abs) against type I IFNs, reported in diagnosed in two individuals aged 49 and paired the production of type I IFN by pDCs an accompanying paper, had undetectable 50 years, and AR IFNAR1 deficiency was diag- stimulated with SARS-CoV-2, whereas AR and levels of serum IFN-a (29). Moreover, none of nosed in two individuals aged 26 and 38 years, AD deficiencies of TLR3 or AR deficiency of the 23 patients with LOF mutations of the and none of the four patients had a prior IFNAR1 impaired fibroblast-intrinsic type I eight genes had detectable auto-Abs against history of life-threatening infections (Table 1). IFN immunity to SARS-CoV2. They also sug- type I IFNs (29), strongly suggesting that the One patient with IRF7 deficiency was tested gest that heterozygosity for LOF variations at two mechanisms of disease are similar but and was seropositive for several common vi- the other five mutated loci also underlie life- independent. Excluding patients with auto- ruses, including various influenza A and B vi- threatening COVID-19. Abs against type I IFN from the burden test ruses (figs. S10 and S11). These genetic defects of pLOF variants at the 12 autosomal loci therefore display incomplete penetrance for Impaired production of type I IFNs in strengthened the association signal (P = 0.007; influenza respiratory distress and only man- patients in vivo OR = 8.97; 95% CI = 1.13 to 71.09). ifested clinically upon infection with the more We tested whether these genotypes impaired virulent SARS-CoV-2. the production of type I IFN in vivo during the Inborn errors of TLR3- and IRF7-dependent course of SARS-CoV-2 infection. We measured type I immunity underlie critical COVID-19 Conclusion the levels of the 13 types of IFN-a in the blood Collectively, our data suggest that at least 23 of The AR form of IFNAR1 deficiency highlights of patients during the acute phase of COVID-19. the 659 patients with life-threatening COVID-19 the importance of type I IFN production rela- We found that 10 of the 23 patients with pneumonia studied had known (six disorders) tive to type III IFN production, which is also mutations for whom samples were available or new (four disorders) genetic defects at eight impaired by defects of TLR3, IRF7, and IRF9 (one with AR IRF7 deficiency, four with AD loci involved in the TLR3- and IRF7-dependent (5). This conclusion is also supported by our IRF7 deficiency, one with AD TLR3 deficiency, induction and amplification of type I IFNs. accompanying report of neutralizing auto-Abs two with AD TBK1 deficiency, one with AR This discovery reveals the essential role of against type I IFNs, but not type III IFNs, in IFNAR1 deficiency, and one with AD TICAM1 both the double-stranded RNA sensor TLR3 other patients with life-threatening COVID-19 deficiency) had serum IFN-a levels <1 pg/ml and type I IFN cell-intrinsic immunity in the pneumonia (29). Inborn errors of TLR3- and Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 6 of 13 RES EARCH | R E S E A R C H A R T I C L E IRF7-dependent type I IFN immunity at eight Mock SARS-CoV-2 loci were found in as many as 23 patients (3.5%) 100 100 of various ages (17 to 77 years) and ancestries (various nationalities from Asia, Europe, Latin 80 80 America, and the Middle East) and in patients 60 60 untreated of both sexes (Table 1). Our findings suggest 40 40 that there may be mutations in other type I TLR3 WT/WT IFN–related genes in other patients with life- 20 20 TLR3 P554S/WT threatening COVID-19 pneumonia. They also TLR3 P554S/E746* suggest that the administration of type I IFN 0 0 100 -2 0 2 100 -2 0 2 may be of therapeutic benefit in selected patients, at least early in the course of SARS- 80 80 CoV-2 infection. 60 60 IFN- Methods 40 40 Patients 20 20 We included in this study 659 patients with life-threatening COVID-19 pneumonia, defined 0 0 -2 0 2 -2 0 2 as patients with pneumonia who developed critical disease, whether pulmonary with mech- Mock SARS-CoV-2 anical ventilation (CPAP, BIPAP, intubation, 100 100 hi-flow oxygen), septic shock, or with any other 80 80 organ damage requiring admission to the 60 60 intensive care unit. Patients who developed untreated Kawasaki-like syndrome were excluded. The S-protein positive (%) 40 40 age of the patients ranged from 0.1 to 99 years, 20 20 IRF7 F410V/Q421* with a mean age of 51.8 years (SD 15.9 years), IRF7 F410V/Q421* + LUC and 25.5% of the patients were female. As con- 0 0 -2 0 2 -2 0 2 IRF7 F410V/Q421* + WT trols, we enrolled 534 individuals infected 100 100 with SARS-CoV-2 based on a positive poly- 80 80 merase chain reaction (PCR) and/or serologi- cal test and/or the presence of typical symptoms Downloaded from https://www.science.org on March 04, 2022 60 60 IFN- such as anosmia or ageusia after exposure to 40 40 a confirmed COVID-19 case, who remained 20 20 asymptomatic or developed mild, self-healing, ambulatory disease. 0 0 -2 0 2 -2 0 2 Next-generation sequencing Mock SARS-CoV-2 Genomic DNA was extracted from whole blood. 100 100 For the 1193 patients and controls included, 80 80 the whole exome (N = 687) or whole genome 60 60 untreated (N = 506) was sequenced. We used the Ge- nome Analysis Software Kit (GATK) (version 40 40 3.4-46 or 4) best-practice pipeline to analyze IFNAR1 WT/WT + EV 20 20 IFNAR1 WT/WT + WT our whole-exome–sequencing data (30). We IFNAR1 V225fs/V225fs + EV aligned the reads obtained with the human 0 0 100 -2 0 2 100 -2 0 2 IFNAR1 V225fs/V225fs + WT reference genome (hg19) using the maximum exact matches algorithm in Burrows–Wheeler 80 80 Aligner software (31). PCR duplicates were re- 60 60 moved with Picard tools (http://broadinstitute. IFN- github.io/picard/). The GATK base quality score 40 40 recalibrator was applied to correct sequencing 20 20 artifacts. 0 0 All of the variants were manually curated -2 0 2 -2 0 2 using Integrative Genomics Viewer (IGV) and S-protein MFI (z-score) confirmed to affect the main functional pro- tein isoform by checking the protein sequence Fig. 6. Cell-intrinsic type I IFN response to SARS-CoV-2. SV40-Fib cells of TLR3−/−, TLR3+/−, IRF7−/−, before inclusion in further analyzes. The main and IRF7−/− SV40-Fib cells rescued with WT IRF7; IFNAR1−/− SV40-Fib cells, and IFNAR1−/− SV40-Fib cells functional protein isoforms were TLR3 (NM_ rescued with WT IFNAR1 were transduced with ACE2 and TMPRSS2 and then either left untreated or treated with 003265), UNC93B1 (NM_030930.4), TICAM1 IFN-b for 4 hours. Cells were then infected with SARS-CoV-2 (MOI = 0.5). After staining, ACE2 and viral (NM_182919), TRAF3 (NM_145725.2), TBK1 S-protein levels were measured by high-content microscopy with gating on ACE2+ cells. IRF7-deficient (NM_013254.4), IRF3 (NM_001571), IRF7 (NM_ SV40-Fib cells were previously transduced with either WT IRF7 or negative control (Luc). IFNAR1-deficient 001572.5), IFNAR1 (NM_000629.3), IFNAR2 cells were previously transduced with either WT IFNAR1 or empty vector (EV). (NM_001289125.3), STAT1 (NM_007315.4), STAT2 Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 7 of 13 RES EARCH | R E S E A R C H A R T I C L E -7 luciferase reporter, and pRL-TK-Renilla lucif- Fig. 7. In vivo type I P erase reporter. Reporter activity was measured IFN responses to 60 with the Dual-Luciferase Reporter Assay Sys- SARS-CoV-2 infections. tem (Promega) according to the manufacturer’s Plasma levels of 13 IFN-a instructions. Firefly luciferase activity was nor- were measured by malized against Renilla luciferase activity and Simoa. Auto-Ab(+) with- expressed as a fold change. TRAF3-deficient out LOF variants indi- human embryonic kidney (HEK) 293T cells cates COVID-19 patients 40 were kindly provided by M. Romanelli (39). with neutralizing anti-IFN- a auto-Abs in our pDC activation by SARS-CoV-2 and accompanying report cytokine production IFN- (pg/ml) (29). P values indicated pDCs from an IRF7−/− patient and a healthy were evaluated using donor matched for age and sex were cultured one-way ANOVA. 20 in the presence of medium alone, influenza virus (A/PR/8/34, 2 mg/ml; Charles River Lab- oratories), or the SARS-CoV-2 primary strain 220_95 (GISAID accession ID: EPI_ISL_469284) at a multiplicity of infection (MOI) of 2. After 12 hours of culture, pDC supernatant was collected for cytokine quantification. IFN-a2 1.0 levels were measured using CBA analyzis (BD Biosciences) in accordance with the manu- facturer’s protocol using a 20 pg/ml detection limit. IFN-l1 secretion was measured in an 0.5 ELISA (R&D Systems, DuoSet DY7246), in ac- cordance with the manufacturer’s instructions. SARS-CoV-2 infection in patient SV40-Fib 0.0 To make patient-derived fibroblasts permis- F7 1 1 s 1 s 3 F7 R M nt K nt R IR sive to SARS-CoV-2 infection, we delivered A TB A IR ria TL ria N AR IC F va D va human ACE2 and TMPRSS2 cDNA to cells by D D T Downloaded from https://www.science.org on March 04, 2022 I A A A R D ith LOF F A A lentivirus transduction using a modified SCRPSY O tL ut vector (GenBank ID: KT368137.1). SARS-CoV-2 ou po tho strain USA-WA1/2020 was obtained from BEI i w w g Resources. ACE2/TMPRSS2-transduced cells were s ne either left untreated or treated with 500 U/ml b b -A -A to IFN-b (11415-1, PBL Assay Science) 4 hours be- to au au fore infection. Cells were infected with SARS- CoV-2 (MOI = 0.5) for 1 hour at 37°C. After 24 hours of infection, cells were fixed and (NM_005419.4), and IRF9 (NM_006084.5). counted for the ethnic heterogeneity of the taken out of the BSL3 for staining. The analysis of IKBKG was customized to un- cohorts by including the first three principal After fixation, cells were stained with SARS- mask the duplicated region in IKBKG using a components of the PCA in the logistic regres- CoV-2 and ACE2 primary antibodies (0.5 and specific pipeline previously described (32). We sion model. PC adjustment is a common and 1 mg/ml, respectively). Primary antibodies were searched the next-generation–sequencing data efficient strategy for accounting for different as follows: for SARS-CoV-2, human monoclonal for deletions in the 13 genes of interest using ancestries of patients and controls in the study anti-spike-SARS-CoV-2 C121 antibody (40), and both the HMZDelFinder (33) and CANOES of rare variants (35–38). We checked that our for ACE2, mouse monoclonal Alexa Fluor 488– (34) algorithms. adjusted burden test was well calibrated by conjugated antibody (FAB9332G-100UG, R&D Sys- also performing an analysis of enrichment in tems). Images were acquired with an ImageXpress Statistical analysis rare (MAF <0.001) synonymous variants of the Micro XLS microscope (Molecular Devices) We performed an enrichment analysis on our 12 genes. PCA was performed with Plink ver- using the 4× objective. MetaXpress software cohort of 659 patients with life-threatening sion 1.9 software on whole-exome– and whole- (Molecular Devices) was used to obtain single- COVID-19 pneumonia and 534 SARS-CoV2– genome–sequencing data and the 1000 Genomes cell mean fluorescence intensity (MFI) values. infected controls, focusing on 12 autosomal (1kG) Project phase 3 public database as a Data analysis on single-cell MFI values was IFN-related genes. We considered variants reference, using 27,480 exonic variants with a done in the R environment (version 4.0.2). that were pLOF with a MAF <0.001 (gnomAD MAF >0.01 and a call rate >0.99. The OR was ACE2/TMPRSS2-transduced cells were classi- version 2.1.1) after experimentally demonstrat- also estimated by logistic regression and ad- fied as ACE2 positive when the ACE2 log MFI ing that all of the pLOF variants seen in the justed for ethnic heterogeneity. was superior to the log mean MFI of mock- cases were actually LOF. We compared the transduced cells plus 2.5 SDs. We excluded proportion of individuals carrying at least Reporter assays all wells with <150 ACE2-positive cells before one pLOF variant of the 12 autosomal genes Cell lines or SV40-Fib cells with known defects SARS-CoV-2 scoring. ACE2-expressing cells in cases and controls by means of logistic re- were transiently or stably transfected with were classified SARS-CoV-2 positive when the gression with the likelihood ratio test. We ac- WT, mutant variants, IFN-b- or ISRE-firefly fluorescence intensity value was superior to Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 8 of 13 RES EARCH | R E S E A R C H A R T I C L E the MFI of mock-infected cells plus 4 SDs. 18. S. Hambleton et al., STAT2 deficiency and susceptibility to 39. S. Fochi et al., TRAF3 Is Required for NF-kB Pathway The median SARS-CoV-2 MFI and percentage viral illness in humans. Proc. Natl. Acad. Sci. U.S.A. 110, Activation Mediated by HTLV Tax Proteins. Front. Microbiol. 10, 3053–3058 (2013). doi: 10.1073/pnas.1220098110; 1302 (2019). doi: 10.3389/fmicb.2019.01302; pmid: 31244811 SARS-CoV-2–positive cells were calculated for pmid: 23391734 40. D. F. Robbiani et al., Convergent antibody responses to each well (independent infection). 19. R. Döffinger et al., X-linked anhidrotic ectodermal dysplasia SARS-CoV-2 in convalescent individuals. Nature 584, with immunodeficiency is caused by impaired NF-kappaB 437–442 (2020). doi: 10.1038/s41586-020-2456-9; Single-molecule array (Simoa) IFN-a signaling. Nat. Genet. 27, 277–285 (2001). doi: 10.1038/85837; pmid: 32555388 pmid: 11242109 41. Q. Zhang, P. Bastard, Z. Liu, J. Le Pen, M. Moncada-Velez, J. Chen, digital ELISA M. Ogishi, I. K. D. Sabli, S. Hodeib, C. Korol, J. Rosain, K. Bilguvar, 20. S. Y. Zhang et al., TLR3 deficiency in patients with herpes Serum IFN-a concentrations were deter- simplex encephalitis. Science 317, 1522–1527 (2007). J. Ye, A. Bolze, B. Bigio, R. Yang, A. Augusto Arias Sierra, doi: 10.1126/science.1139522; pmid: 17872438 Q. Zhou, Y. Zhang, F. Onodi, S. Korniotis, L. Karpf, Q. Philippot, mined using Simoa technology, with reagents 21. G. Zhang et al., A proline deletion in IFNAR1 impairs IFN- M. Chbihi, L. Bonnet-Madin, K. Dorgham, N. Smith, and procedures obtained from Quanterix Cor- signaling and underlies increased resistance to tuberculosis in W. M. Schneider, B. S. Razooky, H.-H. Hoffmann, E. Michailidis, poration (Quanterix SimoaTM IFNa Reagent humans. Nat. Commun. 9, 85 (2018). doi: 10.1038/s41467-017- L. Moens, J. E. Han, L. Lorenzo, L. Bizien, P. Meade, A.-L. Neehus, 02611-z; pmid: 29311663 A. C. Ugurbil, A. Corneau, G. Kerner, P. Zhang, F. Rapaport, Kit, Lexington, MA, USA). According to the 22. M. M. Thomsen et al., Identification of an IRF3 variant and Y. Seeleuthner, J. Manry, C. Masson, Y. Schmitt, A. Schlüter, manufacturer’s instructions, the working dilu- defective antiviral interferon responses in a patient with severe T. Le Voyer, T. Khan, J. Li, J. Fellay, L. Roussel, M. Shahrooei, tions were 1:2 for all sera in working volumes influenza. Eur. J. Immunol. 49, 2111–2114 (2019). doi: 10.1002/ M. F. Alosaimi, D. Mansouri, H. Al-Saud, F. Al-Mulla, F. Almourfi, of 170 ml. eji.201848083; pmid: 31250433 S. Z. Al-Muhsen, F. Alsohime, S. Al Turki, R. Hasanato, 23. M. M. Thomsen et al., Defective interferon priming and D. van de Beek, A. Biondi, L. R. Bettini, M. D’Angio, P. Bonfanti, impaired antiviral responses in a patient with an IRF7 variant L. Imberti, A. Sottini, S. Paghera, E. Quiros-Roldan, C. Rossi, and severe influenza. Med. Microbiol. Immunol. (Berl.) A. J. Oler, M. F. Tompkins, C. Alba, I. Vandernoot, J.-C. Goffard, 208, 869–876 (2019). doi: 10.1007/s00430-019-00623-8; G. Smits, I. Migeotte, F. Haerynck, P. Soler-Palacin, A. Martin-Nalda, RE FE RENCES AND N OT ES pmid: 31172279 R. Colobran, P.-E. Morange, S. Keles, F. Çölkesen, T. Ozcelik, 1. D. M. Morens, A. S. Fauci, Emerging pandemic diseases: How 24. S. G. Tangye et al., Human inborn errors of immunity: 2019 K. K. Yasar, S. Senoglu, Ş. N. Karabela, C. Rodríguez-Gallego, we got to COVID-19. Cell 182, 1077–1092 (2020). doi: 10.1016/ update on the classification from the International Union of G. Novelli, S. Hraiech, Y. Tandjaoui-Lambiotte, X. Duval, j.cell.2020.08.021; pmid: 32846157 Immunological Societies Expert Committee. J. Clin. Immunol. C. Laouenan, COVID-STORM Clinicians, COVID Clinicians, Imagine 2. J. L. Casanova, L. Abel, Lethal Infectious Diseases as Inborn 40, 24–64 (2020). doi: 10.1007/s10875-019-00737-x; COVID Group, French COVID Cohort Study Group, CoV-Contact Errors of Immunity: Toward a Synthesis of the Germ and pmid: 31953710 Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Genetic Theories. Annu. Rev. Pathol. (2020). pmid: 32289233 25. A. Bousfiha et al., Human Inborn Errors of Immunity: 2019 Effort, NIAID-USUHS/TAGC COVID Immunity Group, A. L. Snow, 3. J. L. Casanova, L. Abel, The human genetic determinism of life- Update of the IUIS Phenotypical Classification. J. Clin. C. L. Dalgard, J. Milner, D. C. Vinh, T. H. Mogensen, N. Marr, threatening infectious diseases: Genetic heterogeneity and Immunol. 40, 66–81 (2020). doi: 10.1007/s10875-020- A. N. Spaan, B. Boisson, S. Boisson-Dupuis, J. Bustamante, A. Puel, physiological homogeneity? Hum. Genet. 139, 681–694 (2020). 00758-x; pmid: 32048120 M. Ciancanelli, I. Meyts, T. Maniatis, V. Soumelis, A. Amara, doi: 10.1007/s00439-020-02184-w; pmid: 32462426 26. L. D. Notarangelo, R. Bacchetta, J.-L. Casanova, H. C. Su, M. Nussenzweig, A. García-Sastre, F. Krammer, A. Pujol, D. Duffy, 4. J. L. Casanova, H. C. Su; COVID Human Genetic Effort, A global Human inborn errors of immunity: An expanding universe. R. Lifton, S.-Y. Zhang, G. Gorochov, V. Béziat, E. Jouanguy, effort to define the human genetics of protective immunity to Sci. Immunol. 5, eabb1662 (2020). doi: 10.1126/sciimmunol. V. Sancho-Shimizu, C. M. Rice, L. Abel, L. D. Notarangelo, A. Cobat, SARS-CoV-2 infection. Cell 181, 1194–1199 (2020). abb1662; pmid: 32651211 H. C. Su, J.-L. Casanova, Detailed genotype counts for all coding doi: 10.1016/j.cell.2020.05.016; pmid: 32405102 27. J. Hadjadj et al., Impaired type I interferon activity and variants for: Inborn errors of type I IFN immunity in patients with 5. Q. Zhang, Human genetics of life-threatening influenza inflammatory responses in severe COVID-19 patients. life-threatening COVID-19, Dryad (2020). doi: 10.5061/ pneumonitis. Hum. Genet. 139, 941–948 (2020). doi: 10.1007/ Science 369, 718–724 (2020). doi: 10.1126/science.abc6027; dryad.8pk0p2nkk s00439-019-02108-3; pmid: 32025908 pmid: 32661059 Downloaded from https://www.science.org on March 04, 2022 6. H. K. Lim et al., Severe influenza pneumonitis in children with 28. S. Trouillet-Assant et al., Type I IFN immunoprofiling in AC KNOWLED GME NTS inherited TLR3 deficiency. J. Exp. Med. 216, 2038–2056 COVID-19 patients. J. Allergy Clin. Immunol. 146, 206–208.e2 (2019). doi: 10.1084/jem.20181621; pmid: 31217193 We thank the patients, their families, and healthy donors for (2020). doi: 10.1016/j.jaci.2020.04.029; pmid: 32360285 7. M. J. Ciancanelli et al., Life-threatening influenza and impaired placing their trust in us; Y. Nemirowskaya, D. Papandrea, 29. P. Bastard et al., Auto-antibodies against type I IFNs in patients interferon amplification in human IRF7 deficiency. Science 348, M. Woollet, D. Liu, C. Rivalain, and C. Patissier for administrative with life-threatening COVID-19. Science 10.1126/science. 448–453 (2015). doi: 10.1126/science.aaa1578; pmid: 25814066 assistance; A. Adeleye, D. Bacikova, E. McGrath Martinez, abd4585 (2020). 8. N. Hernandez et al., Life-threatening influenza pneumonitis A. R. Soltis, K. Dobbs, J. Danielson, H. Matthews, and S. Weber 30. M. A. DePristo et al., A framework for variation discovery in a child with inherited IRF9 deficiency. J. Exp. Med. 215, for technical and other assistance; M. M. A. Ata and F. Al Ali for and genotyping using next-generation DNA sequencing 2567–2585 (2018). doi: 10.1084/jem.20180628; their contribution to VirScan experiments; S. Elledge (Brigham and data. Nat. Genet. 43, 491–498 (2011). doi: 10.1038/ng.806; pmid: 30143481 Women’s Hospital and Harvard Medical School, Boston, MA) for pmid: 21478889 9. V. Sancho-Shimizu et al., Herpes simplex encephalitis in kindly providing the VirScan phage library used in this study; 31. H. Li, R. Durbin, Fast and accurate short read alignment children with autosomal recessive and dominant TRIF A. W. Ashbrook, the BSL3 manager of the Rice laboratory assistance; with Burrows-Wheeler transform. Bioinformatics 25, deficiency. J. Clin. Invest. 121, 4889–4902 (2011). M. Lazzaro, Director of Immigration and Academic Appointments, 1754–1760 (2009). doi: 10.1093/bioinformatics/btp324; doi: 10.1172/JCI59259; pmid: 22105173 for assistance; W. Chung, K. Kiryluk, S. O'Byrne, D. Pendrick, pmid: 19451168 10. A. Casrouge et al., Herpes simplex virus encephalitis in J. Williamson, C. Andrews, and M. Disco in the J.M. lab for assistance; 32. B. Boisson et al., Rescue of recurrent deep intronic mutation M. Andreoni (Tor Vergata, Italy) for his clinical contribution; and human UNC-93B deficiency. Science 314, 308–312 (2006). underlying cell type-dependent quantitative NEMO deficiency. A. Novelli (Bambino Gesù Hospital, Italy) for his collaboration. We doi: 10.1126/science.1128346; pmid: 16973841 J. Clin. Invest. 129, 583–597 (2019). doi: 10.1172/JCI124011; thank the GEN-COVID Multicenter study (https://sites.google. 11. R. Pérez de Diego et al., Human TRAF3 adaptor molecule pmid: 30422821 com/dbm.unisi.it/gen-covid). This study used the high-performance deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33. T. Gambin et al., Homozygous and hemizygous CNV detection computational resources of the National Institutes of Health 33, 400–411 (2010). doi: 10.1016/j.immuni.2010.08.014; from exome sequencing data in a Mendelian disease cohort. (NIH) HPC Biowulf cluster (http://hpc.nih.gov) and the Office of pmid: 20832341 Nucleic Acids Res. 45, 1633–1648 (2017). pmid: 27980096 Cyber Infrastructure and Computational Biology (OCICB) High 12. M. Herman et al., Heterozygous TBK1 mutations impair TLR3 34. D. Backenroth et al., CANOES: Detecting rare copy Performance Computing (HPC) cluster at the National Institute of immunity and underlie herpes simplex encephalitis of number variants from whole exome sequencing data. Allergy and Infectious Diseases (NIAID), Bethesda, MD. The childhood. J. Exp. Med. 209, 1567–1582 (2012). doi: 10.1084/ Nucleic Acids Res. 42, e97 (2014). doi: 10.1093/nar/gku345; opinions and assertions expressed herein are those of the authors jem.20111316; pmid: 22851595 pmid: 24771342 and are not to be construed as reflecting the views of the 13. L. L. Andersen et al., Functional IRF3 deficiency in a patient 35. M. Bouaziz, J. Mullaert, B. Bigio, Y. Seeleuthner, J.-L. Casanova, Uniformed Services University of the Health Sciences (USUHS) or with herpes simplex encephalitis. J. Exp. Med. 212, 1371–1379 A. Alcais, L. Abel, A. Cobat, Controlling for human population the U.S. Department of Defense (DoD). Funding: This work was (2015). doi: 10.1084/jem.20142274; pmid: 26216125 stratification in rare variant association studies. bioRxiv supported by a generous donation from the Fisher Center for 14. M. Audry et al., NEMO is a key component of NF-kB- and 969477 [Preprint]. 28 February 2020. .doi: 10.1101/ Alzheimer’s Research Foundation. The Laboratory of Human IRF-3-dependent TLR3-mediated immunity to herpes simplex 2020.02.28.969477 Genetics of Infectious Diseases is supported by the Howard virus. J. Allergy Clin. Immunol. 128, 610–617.e4 (2011). 36. E. Persyn, R. Redon, L. Bellanger, C. Dina, The impact of a Hughes Medical Institute, the Rockefeller University, the St. Giles doi: 10.1016/j.jaci.2011.04.059; pmid: 21722947 fine-scale population stratification on rare variant association Foundation, the NIH (R01AI088364), the National Center for 15. N. Hernandez et al., Inherited IFNAR1 deficiency in otherwise test results. PLOS ONE 13, e0207677 (2018). doi: 10.1371/ Advancing Translational Sciences (NCATS), the NIH Clinical and healthy patients with adverse reaction to measles and yellow journal.pone.0207677; pmid: 30521541 Translational Science Award (CTSA) program (UL1 TR001866), a fever live vaccines. J. Exp. Med. 216, 2057–2070 (2019). 37. Y. Zhang, X. Shen, W. Pan, Adjusting for population Fast Grant from Emergent Ventures, Mercatus Center at George doi: 10.1084/jem.20182295; pmid: 31270247 stratification in a fine scale with principal components and Mason University, the Yale Center for Mendelian Genomics and the 16. C. J. Duncan et al., Human IFNAR2 deficiency: Lessons for sequencing data. Genet. Epidemiol. 37, 787–801 (2013). GSP Coordinating Center funded by the National Human Genome antiviral immunity. Sci. Transl. Med. 7, 307ra154 (2015). doi: 10.1002/gepi.21764; pmid: 24123217 Research Institute (NHGRI) (UM1HG006504 and U24HG008956), doi: 10.1126/scitranslmed.aac4227; pmid: 26424569 38. S. Boisson-Dupuis et al., Tuberculosis and impaired the French National Research Agency (ANR) under the 17. S. Dupuis et al., Impaired response to interferon-alpha/beta IL-23-dependent IFN-g immunity in humans homozygous for a “Investments for the Future” program (ANR-10-IAHU-01), the and lethal viral disease in human STAT1 deficiency. Nat. Genet. common TYK2 missense variant. Sci. Immunol. 3, eaau8714 Integrative Biology of Emerging Infectious Diseases Laboratory of 33, 388–391 (2003). doi: 10.1038/ng1097; pmid: 12590259 (2018). doi: 10.1126/sciimmunol.aau8714; pmid: 30578352 Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 9 of 13 RES EARCH | R E S E A R C H A R T I C L E Medical Research (FRM) (EQU201903007798), the FRM and ANR The authors declare no competing financial interests. J.-L.C. is Cathérine Heijmans101, María Soledad Holanda-Peña102, GENCOVID project, ANRS-COV05, the Square Foundation, listed as an inventor on patent application US63/055,155 filed by Juan Pablo Horcajada103, Levi Hoste104, Eric Hoste105, Sami Hraiech106, Grandir–Fonds de Solidarité pour l’Enfance, the SCOR Corporate The Rockefeller University that encompasses aspects of this Linda Humbert107, Alejandro D. Iglesias108, Antonio Íñigo-Campos91, Foundation for Science, Institut National de la Santé et de la publication. R.L. is a non-executive director of Roche and its Matthieu Jamme109, María Jesús Arranz110, Iolanda Jordan111, Recherche Médicale (INSERM), the University of Paris. The French subsidiary Genentech. Data and materials availability: Plasma, Philippe Jorens112, Fikret Kanat113, Hasan Kapakli114, Iskender Kara115, COVID Cohort study group was sponsored by Inserm and cells, and genomic DNA are available from J.-L.C. or D.V. under a Adem Karbuz116, Kadriye Kart Yasar117, Sevgi Keles118, supported by the REACTing consortium and by a grant from the material transfer agreement with Rockfeller University/Research Yasemin Kendir Demirkol119, Adam Klocperk120, Zbigniew J. Król121, French Ministry of Health (PHRC 20-0424). Regione Lombardia, Institute-McGill University Health Centre. pSCRPSY_TMPRSS2- Paul Kuentz122, Yat Wah M. Kwan123, Jean-Christophe Lagier124, Italy (project “Risposta immune in pazienti con COVID-19 e co- 2A-NeoR_ACE2 and Huh-7.5 cells are available upon request from Bart N. Lambrecht33, Yu-Lung Lau125, Fleur Le Bourgeois60, morbidità”), and the Intramural Research Program of the NIAID, C.R. under a material transfer agreement with The Rockefeller Yee-Sin Leo126, Rafael Leon Lopez127, Daniel Leung125, Michael Levin128, NIH. The laboratory of Genomes & Cell Biology of Disease is University, or The Rockefeller University and Apath, LLC, Michael Levy60, Romain Lévy20, Zhi Li49, Agnes Linglart129, supported by “Integrative Biology of Emerging Infectious Diseases” respectively. Clinical data, DNA, and other patient samples are Bart Loeys130, José M. Lorenzo-Salazar91, Céline Louapre131, (grant no. ANR-10-LABX-62-IBEID), the “Fondation pour la available from the Amsterdam UMC Covid-19 Biobank (D.v.d.B.) Catherine Lubetzki131, Charles-Edouard Luyt132, David C. Lye133, Recherche Medicale” (grant FRM–EQU202003010193), the under a material transfer agreement with Amsterdam UMC. Davood Mansouri134, Majid Marjani135, Jesus Marquez Pereira136, “Agence Nationale de la Recherche” (ANR FLASH COVID project Material and reagents used are almost exclusively commercially Andrea Martin137, David Martínez Pueyo138, Javier Martinez-Picado139, IDISCOVR cofounded by the “Fondation pour la Recherche available and nonproprietary. Requests for materals derived from Iciar Marzana140, Alexis Mathian14, Larissa R. B. Matos37, Médicale”), University of Paris (“Plan de Soutien Covid-19”: human samples may be made available, subject to any underlying Gail V. Matthews141, Julien Mayaux142, Jean-Louis Mège143, RACPL20FIR01-COVID-SOUL). I.M. is a senior clinical investigator restrictions on such samples. J.-L.C. can make material transfer Isabelle Melki144, Jean-François Meritet145, Ozge Metin146, with the FWO Vlaanderen; I.M. and L.M. are supported by FWO agreements available through The Rockefeller University. Detailed Isabelle Meyts147, Mehdi Mezidi148, Isabelle Migeotte149, G0C8517N – GOB5120N. The VS team was supported by “Agence genotype counts for all coding variants in the genes investigated in Maude Millereux150, Tristan Mirault151, Clotilde Mircher67 , Nationale de la Recherche” (ANR-17-CE15-0003, ANR-17-CE15- this manuscript are available at Dryad (41). The whole-genome Mehdi Mirsaeidi 152 , Abián Montesdeoca Melián153, 0003-01) and by Université de Paris “PLAN D’URGENCE COVID19”. sequencing datasets used for the analyses, including critical Antonio Morales Martinez154, Pierre Morange155, Clémence Mordacq107, L.K. was supported by a fellowship from the French Ministry of patients and asymptomatic controls described in this manuscript, Guillaume Morelle156, Stéphane Mouly13, Adrián Muñoz-Barrera91, Research. V.S.-S. is supported by a UKRI Future Leaders were deposited in dbGaP under accession number phs002245.v1. Leslie Naesens157, Cyril Nafati158, João Farela Neves159, Lisa FP. Ng160, Fellowship (MR/S032304/1). S.Z.A.-M. is supported by the Elite p1. All other data are available in the manuscript or the Yeray Novoa Medina161, Esmeralda Nuñez Cuadros162, Journals Program at King Saud University through grant no. supplementary material. This work is licensed under a Creative J. Gonzalo Ocejo-Vinyals163, Zerrin Orbak164, Mehdi Oualha20, PEJP-16-107. The J.M. laboratory is supported by Columbia Commons Attribution 4.0 International (CC BY 4.0) license, which Tayfun Özçelik165, Qiang Pan-Hammarström166, Christophe Parizot142, University COVID biobank and grant no. UL1TR001873. Work in the permits unrestricted use, distribution, and reproduction in any Tiffany Pascreau167, Estela Paz-Artal168, Sandra Pellegrini49, Laboratory of Virology and Infectious Disease was supported by medium, provided the original work is properly cited. To view a Rebeca Pérez de Diego84, Aurélien Philippe169, Quentin Philippot77, NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707- copy of this license, visit https://creativecommons.org/licenses/ Laura Planas-Serra170, Dominique Ploin171, Julien Poissy172, 10S1; a George Mason University Fast Grant; and the G. Harold and by/4.0/. This license does not apply to figures/photos/artwork or Géraldine Poncelet43, Marie Pouletty173, Paul Quentric142, Leila Y. Mathers Charitable Foundation. J.L.P. is supported by a other content included in the article that is credited to a third Didier Raoult143, Anne-Sophie Rebillat67, Ismail Reisli174, Pilar Ricart175, European Molecular Biology Organization Long-Term Fellowship party; obtain authorization from the rights holder before using Jean-Christophe Richard176, Nadia Rivet28, Jacques G. Rivière177, (ALTF 380-2018). Work at the Neurometabolic Diseases such material. Gemma Rocamora Blanch15, Carlos Rodrigo1, Carlos Rodriguez-Gallego178, Laboratory received funding from the European Union’s Horizon Agustí Rodríguez-Palmero179, Carolina Soledad Romero180, 2020 research and innovation program under grant no. 824110 COVID-STORM Clinicians Giuseppe Foti1, Giacomo Bellani1, Anya Rothenbuhler181, Flore Rozenberg182, Maria Yolanda Ruiz del Prado183, (EasiGenomics grant no. COVID-19/PID12342) to A.P., and Roche Giuseppe Citerio1, Ernesto Contro1, Alberto Pesci2, Joan Sabater Riera15, Oliver Sanchez184, Silvia Sánchez-Ramón185, and Illumina Covid Match Funds to M.G.. C.R.G. and colleagues are Maria Grazia Valsecchi3, Marina Cazzaniga4 Agatha Schluter170, Matthieu Schmidt186, Cyril E. Schweitzer187, supported by Instituto de Salud Carlos III (COV20_01333 and Francesco Scolari188, Anna Sediva189, Luis M. Seijo190, Damien Sene13, COV20_01334), Spanish Ministry of Science and Innovation, with 1 Department of Emergency, Anesthesia and Intensive Care, School Sevtap Senoglu117, Mikko R. J. Seppänen191, Alex Serra Ilovich192, the funding of European Regional Development Fund-European of Medicine and Surgery, University of Milano-Bicocca, San Mohammad Shahrooei62, Hans Slabbynck193, David M. Smadja194, Ali Downloaded from https://www.science.org on March 04, 2022 Social Fund -FEDER-FSE; (RTC-2017-6471-1; AEI/FEDER, UE), and Gerardo Hospital, Monza, Italy. 2Department of Pneumology, Sobh195, Xavier Solanich Moreno15, Jordi Solé-Violán196, Catherine Soler197, Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas School of Medicine and Surgery, University of Milano-Bicocca, Pere Soler-Palacín137, Yuri Stepanovskiy198, Annabelle Stoclin199, científicas del ITER para colaborar en la lucha contra la San Gerardo Hospital, Monza, Italy. 3Center of Bioinformatics and Fabio Taccone149, Yacine Tandjaoui-Lambiotte200, Jean-Luc Taupin201, COVID-19”). D.C.V. is supported by the Fonds de la recherche en Biostatistics, School of Medicine and Surgery, University of Simon J. Tavernier202, Benjamin Terrier203, Caroline Thumerelle107, santé du Québec clinician-scientist scholar program. H.S. is Milano-Bicocca, San Gerardo Hospital, Monza, Italy. 4Phase I Gabriele Tomasoni204, Julie Toubiana48, Josep Trenado Alvarez205, adjunct faculty at the University of Pennsylvania. A.-L.N. was Research Center, School of Medicine and Surgery, University of Sophie Trouillet-Assant206, Jesús Troya207, Alessandra Tucci208, supported by the Foundation Bettencourt Schueller. The Milano-Bicocca, San Gerardo Hospital, Monza, Italy. Matilde Valeria Ursini83, Yurdagul Uzunhan209, Pierre Vabres210, Amsterdam UMC Covid-19 Biobank was funded by the Netherlands Juan Valencia-Ramos211, Eva Van Braeckel33, Stijn Van de Velde212, Organization for Health Research and Development (ZonMw, COVID Clinicians Jorge Abad1, Sergio Aguilera-Albesa2, Ana Maria Van Den Rym84, Jens Van Praet213, Isabelle Vandernoot214, NWO-vici 91819627), The Corona Research Fund (Amsterdam UMC), Ozge Metin Akcan3, Ilad Alavi Darazam4, Juan C. Aldave5, Hulya Vatansev215, Valentina Vélez-Santamaria42, Sébastien Viel171, Dr. J. C. Vaillantfonds, and Amsterdam UMC. Work on COVID-19 at Miquel Alfonso Ramos6, Seyed Alireza Nadji7, Gulsum Alkan8, Cédric Vilain216, Marie E. Vilaire67, Audrey Vincent35, Guillaume Voiriot217, the A.G.-S. laboratory is partly supported by NIH supplements to Jerome Allardet-Servent9, Luis M. Allende10, Laia Alsina11, Fanny Vuotto107, Alper Yosunkaya90, Barnaby E. Young126, grants U19AI135972, U19AI142733, and R35 HL135834, and to Marie-Alexandra Alyanakian12, Blanca Amador-Borrero13, Fatih Yucel218, Faiez Zannad219, Mayana Zatz37, Alexandre Belot220* contract HHSN272201800048C, by a DoD supplement to grant Zahir Amoura14, Arnau Antolí15, Sevket Arslan16, Sophie Assant17, W81XWH-20-1-0270, by DARPA project HR0011-19-2-0020, by CRIP Terese Auguet18, Axelle Azot19, Fanny Bajolle20, Aurélie Baldolli21, 1 University Hospital and Research Institute “Germans Trias i Pujol,” (Center for Research on Influenza Pathogenesis), a NIAID funded Maite Ballester22, Hagit Baris Feldman23, Benoit Barrou24, Badalona, Spain. 2Navarra Health Service Hospital, Pamplona, Center of Excellence for Influenza Research and Surveillance (CEIRS, Alexandra Beurton25, Agurtzane Bilbao26, Geraldine Blanchard-Rohner27, Spain. 3Division of Pediatric Infectious Diseases, Necmettin contract HHSN272201400008C), by an NIAID funded Collaborative Ignacio Blanco1, Adeline Blandinières28, Daniel Blazquez-Gamero29, Erbakan University, Meram Medical Faculty, Konya, Turkey. 4 Influenza Vaccine Innovation Center (SEM-CIVIC, contract Marketa Bloomfield30, Mireia Bolivar-Prados31, Raphael Borie32, Department of Infectious Diseases, Loghman Hakim Hospital, 75N93019C00051) and by the generous support of the JPB Cédric Bosteels33, Ahmed A. Bousfiha34, Claire Bouvattier35, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5 Foundation, the Open Philanthropy Project (research grant Oksana Boyarchuk36, Maria Rita P. Bueno37, Jacinta Bustamante20, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru. 6Parc 2020-215611(5384)) and anonymous donors. The Virscan analysis Juan José Cáceres Agra38, Semra Calimli39, Ruggero Capra40, Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain. 7Virology presented in fig. S11 was performed with financial support from Maria Carrabba41, Carlos Casasnovas42, Marion Caseris43, Research Center, National Institutes of Tuberculosis and Lung Sidra Medicine. J.R.H. is supported by Biomedical Advanced Research Martin Castelle44, Francesco Castelli45, Martín Castillo de Vera46, Diseases, Shahid Beheshti University of Medical Sciences, Tehran, and Development Authority under Contract (HHSO10201600031C). Mateus V. Castro37, Emilie Catherinot47, Martin Chalumeau48, Iran. 8Division of Pediatric Infectious Diseases, Faculty of Medicine, Author contributions: A.G., A.A., A.A.A., A.L.S., A.-L.N., Bruno Charbit49, Matthew P. Cheng50, Père Clavé31, Bonaventura Clotet51, Selcuk University, Konya, Turkey. 9Intensive Care Unit, Hôpital A.C., A.C., A.P., B.B., B.S.R., C.A., C.M., C.K., C.L., C.M.R., C.L.D., Anna Codina52, Fatih Colkesen53, Fatma Çölkesen54, Roger Colobran55, Européen, Marseille, France. 10Immunology Department, University D.D., E.M., E.J., F.A., F.A-M., F.O., F.A., F.K., G.N., G.S., G.G., H.-H.H., Cloé Comarmond56, David Dalmau57, David Ross Darley58, Hospital 12 de Octubre, Research Institute imas12, and Complu- H.K.A.S., H.S., I.K.D.S., I.M., J.L.P., J.R., J.E.H., J.C., J.M., J.Y., K.D., Nicolas Dauby59, Stéphane Dauger60, Loic de Pontual61, Amin Dehban62, tense University, Madrid, Spain. 11Clinical Immuology and Primary K.B., L.A., L.L.-D., L.K., L.M., L.B-M., L.B., L.D.N., M.M-V., M.C., M.O., Geoffroy Delplancq63, Alexandre Demoule64, Jean-Luc Diehl65, Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona, M.C., M.N., M.F.T., M.S., M.F.A., N.M., N.S., P.B., P.M., Q.Z., Q.Z., Q.P., Stephanie Dobbelaere66, Sophie Durand67, Waleed Eldars68, Spain. 12Department of Biological Immunology, Necker Hospital for R.L., R.Y., S.A.T., S.Z.A-M., S.H., S.K., S.H., S.B.-D., T.K., T.M., Mohamed Elgamal69, Marwa H. Elnagdy70, Melike Emiroglu71, Sick Children, APHP and INEM, Paris, France. 13Internal Medicine T.H.M., V.S.-S., V.S., V.B., W.S., X.D., Y.S., and Z.L. either performed Emine Hafize Erdeniz72, Selma Erol Aytekin73, Romain Euvrard74, Department, Hôpital Lariboisière, APHP; Université de Paris, Paris, or supervised experiments, generated and analyzed data, and Recep Evcen75, Giovanna Fabio41, Laurence Faivre76, Antonin Falck43, France. 14Internal Medicine Department, Pitié-Salpétrière Hospital, contributed to the manuscript. A.S., A.C.U., A.B., A.O., A.P., B.B., D.V. Muriel Fartoukh77, Morgane Faure78, Miguel Fernandez Arquero79, Paris, France. 15Hospital Universitari de Bellvitge, Barcelona, Spain. 16 D.B., F.R., G.K., J.M., P.Z., S-Y.Z., T.L.-V., Y.S., and Y.Z. performed Carlos Flores80, Bruno Francois81, Victoria Fumadó82, Francesca Fusco83, Division of Clinical Immunology and Allergy, Necmettin Erbakan computational analysis. A.S., A.N.S., A.M.-N., A.B., C.R., D.M., D.C.V., Blanca Garcia Solis84, Pascale Gaussem85, Juana Gil-Herrera86, University, Meram Medical Faculty, Konya, Turkey. 17Joint Research E.Q.-R., F.H., I.M., I.V., J.B., J.-C.G., L.R.B., L.R., L.I., M.D., P.B., P.S.-P., Laurent Gilardin87, Monica Girona Alarcon88, Mònica Girona-Alarcón88, Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, P.-E.M., R.H., R.C., S.K., S.P., T.O., Y.T.-L., K.K., S.S., J.F., and S.N.K. Jean-Christophe Goffard89, Funda Gok90, Rafaela González-Montelongo91, Lyon Sud Hospital, Lyon, France. 18Hospital U. de Tarragona Joan evaluated and recruited patients to COVID and/or control cohorts. Antoine Guerder92, Yahya Gul93, Sukru Nail Guner93, Marta Gut94, XXIII, Universitat Rovira i Virgili (URV), IISPV, Tarragona, Spain. 19 Q.Z. and J.-L.C. wrote the manuscript. All authors edited the Jérôme Hadjadj95, Filomeen Haerynck96, Rabih Halwani97, Private practice, Paris, France. 20Necker Hospital for Sick manuscript. J.-L.C. supervised the project. Competing interests: Lennart Hammarström98, Nevin Hatipoglu99, Elisa Hernandez-Brito100, Children, AP-HP, Paris, France. 21Department of Infectious Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 10 of 13 RES EARCH | R E S E A R C H A R T I C L E Diseases, CHU de Caen, Caen, France. 22Consorcio Hospital Faculty, Konya, Turkey. 76Centre de Génétique, CHU Dijon, Dijon, Hospital, Le Kremlin-Bicêtre, France. 130Department of Medical General Universitario, Valencia, Spain. 23The Genetics Institute, France. 77APHP Tenon Hospital, Paris, France. 78Sorbonne Genetics, University Hospital Antwerp, Antwerp, Belgium. 131Neu- Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Universités, UPMC University of Paris, Paris, France. 79Department rology Unit, APHP Pitié-Salpêtrière Hospital, Paris University, Paris, Tel Aviv University, Tel Aviv, Israel. 24Department of Urology, of Clinical Immunology , Hospital Clínico San Carlos, Madrid, Spain. France. 132Intensive Care Unit, APHP Pitié-Salpêtrière Hospital, 80 Nephrology, and Transplantation, APHP-SU, Sorbonne Université, Genomics Division, Instituto Tecnológico y de Energías Renov- Paris University, Paris, France. 133National Centre for Infectious INSERM U 1082, Paris, France. 25Service de Médecine Intensive– ables (ITER), Santa Cruz de Tenerife, Spain; CIBER de Enferme- Diseases; Tan Tock Seng Hospital; Yong Loo Lin School of Réanimation et Pneumologie, APHP Hôpital Pitié–Salpêtrière, dades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Medicine; Lee Kong Chian School of Medicine, Singapore. Paris, France. 26Cruces University Hospital, Bizkaia, Spain. Research Unit, Hospital Universitario N.S. de Candelaria, Santa 134 Department of Clinical Immunology and Infectious Diseases, 27 Paediatric Immunology and Vaccinology Unit, Geneva University Cruz de Tenerife, Spain; Instituto de Tecnologías Biomédicas (ITB), National Research Institute of Tuberculosis and Lung Diseases, Hospitals and Faculty of Medicine, Geneva, Switzerland. Universidad de La Laguna, San Cristóbal de La Laguna, Spain. Shahid Beheshti University of Medical Sciences, Tehran, Iran. 28 81 135 Hematology, Georges Pompidou Hospital, APHP, Paris, France. CHU Limoges and Inserm CIC 1435 and UMR 1092, Limoges, Clinical Tuberculosis and Epidemiology Research Center, 29 Pediatric Infectious Diseases Unit, Instituto de Investigación 12 France. 82Infectious Diseases Unit, Department of Pediatrics, National Research Institute of Tuberculosis and Lung Diseases de Octubre imas12, and Hospital Universitario 12 de Octubre, Hospital Sant Joan de Déu, Barcelona, Spain; Institut de Recerca (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Madrid, Spain. 30Department of Immunology, Motol University Sant Joan de Déu, Spain; Universitat de Barcelona (UB), Barcelona, Iran. 136Hospital Sant Joan de Déu and University of Barcelona, Hospital, 2nd Faculty of Medicine, Charles University, Department Spain. 83Institute of Genetics and Biophysics “Adriano Buzzati- Barcelona, Spain. 137Pediatric Infectious Diseases and Immunode- of Pediatrics, Thomayer’s Hospital, 1st Faculty of Medicine, Charles Traverso,” IGB-CNR, Naples, Italy. 84Laboratory of Immunogenetics ficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron University, Prague, Czech Republic. 31Centro de Investigación of Human Diseases, IdiPAZ Institute for Health Research, La Paz Research Institute, Vall d’Hebron Barcelona Hospital Campus. Biomédica en Red de Enfermedades Hepàticas y Digestivas Hospital, Madrid, Spain. 85Hematology, APHP, Hopital Européen Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. (Ciberehd), Hospital de Mataró, Consorci Sanitari del Maresme, Georges Pompidou and Inserm UMR-S1140, Paris, France. 86Hos- 138 Hospital Universitari Mutua de Terrassa, Universitat de Barce- Mataró, Spain. 32Service de Pneumologie, Hopital Bichat, APHP, pital General Universitario and Instituto de Investigación Sanitaria lona, Barcelona, Spain. 139IrsiCaixa AIDS Research Institute, ICREA, Paris, France. 33Department of Pulmonology, Ghent University “Gregorio Marañón,” Madrid, Spain. 87Bégin military Hospital, UVic-UCC, Research Institute “Germans Trias i Pujol,” Badalona, Hospital, Ghent, Belgium. 34Clinical Immunology Unit, Pediatric Bégin, France. 88Pediatric Intensive Care Unit, Hospital Sant Joan Spain. 140Department of Laboratory, Cruces University Hospital, Infectious Disease Department, Faculty of Medicine and Pharmacy, de Déu, Barcelona, Spain. 89Department of Internal Medicine, Barakaldo, Bizkaia, Spain. 141University of New South Wales, New Averroes University Hospital, LICIA Laboratoire d’Immunologie Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. South Wales, Australia. 142APHP Pitié-Salpêtrière Hospital, Paris, 90 Clinique, d’Inflammation et d’Allergie, Hassann Ii University, Division of Critical Care Medicine, Department of Anesthesiology France. 143Aix-Marseille University, APHM, Marseille, France. Casablanca, Morocco. 35Endocrinology Unit, APHP Hôpitaux and Reanimation, Necmettin Erbakan University, Meram Medical 144 Robert Debré Hospital, Paris, France. 145APHP Cohin Hospital, Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. 36Department Faculty, Konya, Turkey. 91Genomics Division, Instituto Tecnológico Paris, France. 146Necmettin Erbakan University Meram Faculty of of Children’s Diseases and Pediatric Surgery, I. Horbachevsky y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain. Medicine Department of Pediatric Infectious Diseases, Konya, Ternopil National Medical University, Ternopil, Ukraine. 37Human 92 Assistance Publique Hôpitaux de Paris, Paris, France. 93Division Turkey. 147University Hospitals Leuven, Leuven, Belgium. 148 Genome and Stem-Cell Research Center, University of São Paulo, of Allergy and Immunology, Necmettin Erbakan University, Meram Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, São Paulo, Brazil. 38Hospital Insular, Las Palmas de Gran Canaria, Medical Faculty, Konya, Turkey. 94CNAG-CRG, Centre for Genomic France. 149Hôpital Erasme, Brussels, Belgium. 150CH Gonesse, Spain. 39Division of Critical Care Medicine, Department of Regulation (CRG), Barcelona Institute of Science and Technology Gonesse, France. 151Vascular Medicine, Georges Pompidou Hospi- Anesthesiology and Reanimation, Konya State Hospital, Konya, (BIST); Universitat Pompeu Fabra (UPF), Barcelona, Spain. tal, APHP, Paris, France. 152Division of Pulmonary and Critical Care, Turkey. 40MS Center, Spedali Civili, Brescia, Italy. 41Fondazione 95 Department of Internal Medicine, National Reference Center for University of Miami, Miami, FL, USA. 153Guanarteme Health Care IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. Rare Systemic Autoimmune Diseases, AP-HP, APHP-CUP, Hôpital Center, Canarian Health System, Las Palmas de Gran Canaria, 42 Bellvitge University Hospital, L’Hospitalet de Llobregat, Cochin, Paris, France. 96Ghent University Hospital, Ghent, Belgium. Spain. 154Regional University Hospital of Malaga, Malaga, Spain. Barcelona, Spain. 43Hopital Robert Debré, Paris, France. 44Pediatric 97 Sharjah Institute of Medical Research, College of Medicine, 155 Aix-Marseille Université, Marseille, France. 156Department of Immuno-hematology Unit, Necker Enfants Malades Hospital, University of Sharjah, Sharjah, UAE. 98Department of Laboratory General Paediatrics, Hôpital Bicêtre, AP-HP, University of Paris AP-HP, Paris, France. 45Department of Infectious and Tropical Medicine, SE14186, Huddinge, Karolinska Institutet, Stockholm, Saclay, Le Kremlin-Bicêtre, France. 157Department of Internal Diseases, University of Brescia, ASST Spedali Civili di Brescia, Sweden. 99Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Medicine, Ghent University Hospital, Ghent, Belgium. 158CHU de La Brescia, Italy. 46Doctoral Health Care Center, Canarian Health Konuk Training and Research Hospital, University of Health Timone, Marseille, France. 159Centro Hospitalar Universitário de Downloaded from https://www.science.org on March 04, 2022 System, Las Palmas de Gran Canaria, Spain. 47Hôpital Foch, Sciences, Istanbul, Turkey. 100Department of Immunology, Hospital Lisboa Central, Lisbon, Portugal. 160Infectious Diseases Horizontal Suresnes, France. 48Necker Hospital for Sick Children, Paris Universitario de Gran Canaria Dr. Negrín, Canarian Health System, Technlogy Centre, A*STAR; Singapore Immunology Network, University, AP-HP, Paris, France. 49Pasteur Institute, Paris, France. Las Palmas de Gran Canaria, Spain. 101Department of Pediatric A*STAR, Singapore. 161Department of Pediatrics, Complejo Hospi- 50 McGill University Health Centre, Montreal, Canada. 51University Hemato-Oncology, Jolimont Hospital; Department of Pediatric talario Universitario Insular-Materno Infantil, Canarian Health Hospital and Research Institute “Germans Trias i Pujol,” IrsiCaixa Hemato-Oncology, HUDERF, Brussels, Belgium. 102Intensive Care System, Las Palmas de Gran Canaria, Spain. 162Regional Universi- AIDS Research Institute, UVic-UCC, Badalona, Spain. 52Clinical Unit, Marqués de Valdecilla Hospital, Santander, Spain. 103Hospital tary Hospital of Málaga, Málaga, Spain. 163Hospital Universitario Biochemistry, Pathology, Paediatric Neurology and Molecular del Mar, Parc de Salut Mar, Barcelona, Spain. 104Department of Marqués de Valdecilla, Santander, Spain. 164Faculty of Medicine, Medicine Departments and Biobank, Institut de Recerca Sant Joan Pediatric Pulmonology and Immunology, Ghent University Hospital, Ataturk University, Erzurum, Turkey. 165Department of Molecular de Déu and CIBERER-ISCIII, Esplugues, Spain. 53Division of Clinical Ghent, Belgium. 105Department of Intensive Care Unit, Ghent Biology and Genetics, Bilkent University, Ankara, Turkey. Immunology and Allergy, Department of Internal Medicine, University Hospital, Ghent, Belgium. 106Intensive Care Unit, APHM, 166 Department of Biosciences and Nutrition, Karolinska Institutet, Necmettin Erbakan University, Meram Medical Faculty, Konya, Marseille, France. 107CHU Lille, Lille, France. 108Department of SE14183, Stockholm, Sweden. 167L’Hôpital Foch, Suresnes, France. Turkey. 54Department of Infectious Diseases and Clinical Micro- Pediatrics, Columbia University, New York, NY, USA. 109Centre 168 Department of Immunology, Hospital Universitario 12 de biology, Konya Training and Research Hospital, Konya, Turkey. Hospitalier Intercommunal Poissy Saint Germain en Laye, Poissy, Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre 55 Hospital Universitari Vall d’Hebron, Barcelona, Spain. 56Pitié- France. 110Fundació Docència i Recerca Mútua Terrassa, Terrassa, imas12, Madrid, Spain. 169APHP Hôpitaux Universitaires Paris-Sud, Salpêtrière Hospital, Paris, France. 57Fundació Docència i Recerca Spain. 111Hospital Sant Joan de Déu, Kids Corona Platfform, Le Kremlin-Bicêtre, France. 170Neurometabolic Diseases Labora- Mútua Terrassa, Barcelona, Spain; Hospital Universitari Mutua Barcelona, Spain. 112Department of Intensive Care Unit, University tory, IDIBELL-Hospital Duran i Reynals, Barcelona; CIBERER U759, Terrassa, Universitat de Barcelona, Terrassa, Catalonia, Spain. Hospital Antwerp, Antwerp, Belgium. 113Selcuk University, Faculty ISCiii, Madrid, Spain. 171Hospices Civils de Lyon, Lyon, France. 58 UNSW Medicine, St. Vincent’s Clinical School, and Department of of Medicine, Chest Diseases Department, Konya, Turkey. 114Division 172 Université de Lille, Inserm U1285, CHU Lille, Paris, France. 173 Thoracic Medicine, St. Vincent’s Hospital Darlinghurst, Sidney, of Allergy and Immunology, Balikesir Ataturk City Hospital, Departement of General Pediatrics, University Hospital Robert Australia. 59CHU Saint-Pierre, Université Libre de Bruxelles, Balikesir, Turkey. 115Division of Critical Care Medicine, Selcuk Debré, APHP, Paris, France. 174Necmettin Erbakan University, Brussels, Belgium. 60Pediatric Intensive Care Unit, Robert-Debré University, Faculty of Medicine, Konya, Turkey. 116Division of Konya, Turkey. 175Germans Trias i Pujol Hospital, Badalona, Spain. University Hospital, APHP, Paris, France. 61Sorbonne Paris Nord, Pediatric Infectious Diseases, Prof. Dr. Cemil Tascıoglu City 176 Medical Intensive Care Unit, Hopital de la Croix-Rousse, Hôpital Jean Verdier, APHP, Bondy, France. 62Specialized Immu- Hospital, Istanbul, Turkey. 117Departments of Infectious Diseases Hospices Civils de Lyon, Lyon, France. 177Pediatric Infectious nology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, and Clinical Microbiology, Bakirkoy Dr. Sadi Konuk Training and Diseases and Immunodeficiencies Unit, Hospital Universitari Vall Iran. 63Centre de Génétique Humaine, CHU Besançon, Besançon, Research Hospital, University of Health Sciences, Istanbul, Turkey. d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barce- France. 64Sorbonne Université Médecine and APHP Sorbonne 118 Meram Medical Faculty, Necmettin Erbakan University, Meram lona Hospital Campus., Barcelona, Spain. 178Department of Université Site Pitié-Salpêtrière, Paris, France. 65Intensive Care Medical Faculty, Konya, Turkey. 119Health Sciences University, Immunology, Hospital Universitario de Gran Canaria Dr. Negrín, Unit, Georges Pompidou Hospital, APHP, Paris, France. 66Depart- Umraniye Education and Research Hospital, Istanbul, Turkey. Canarian Health System, Las Palmas de Gran Canaria, Spain. ment of Pneumology, AZ Delta, Roeselare, Belgium. 67Institut 120 Department of Immunology, 2nd Faculty of Medicine, Charles University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Jérôme Lejeune, Paris, France. 68Department of Microbiology and University and University Hospital in Motol, Prague, Czech Spain. 179Neurometabolic Diseases Laboratory, IDIBELL-Hospital Immunology, Faculty of Medicine, Mansoura University, Mansoura, Republic. 121Central Clinical Hospital of Ministry of the Interior and Duran i Reynals, Barcelona, Spain. 180Consorcio Hospital General Egypt. 69Department of Chest, Faculty of Medicine, Mansoura Administration in Warsaw, Warsaw, Poland. 122Oncobiologie Universitario, Valencia, Spain. 181APHP Hôpitaux Universitaires University, Mansoura, Egypt. 70Department of Medical Bio- Génétique Bioinformatique, PC Bio, CHU Besançon, Besançon, Paris-Sud, Paris, France. 182Virology Unit, Université de Paris, chemistry and Molecular Biology, Faculty of Medicine, Mansoura France. 123Paediatric Infectious Disease Unit, Hospital Authority Cohin Hospital, APHP, Paris, France. 183Hospital San Pedro, University, Mansoura, Egypt. 71Faculty of Medicine, Division of Infectious Disease Center, Princess Margaret Hospital, Hong Kong Logroño, Spain. 184Respiratory Medicine, Georges Pompidou Pediatric Infectious Diseases, Selcuk University, Konya, Turkey. (Special Administrative Region), China. 124Aix Marseille University, Hospital, APHP, Paris, France. 185Department of Immunology, 72 Division of Pediatric Infectious Diseases, Ondokuz Mayıs Univer- IRD, MEPHI, IHU Méditerranée Infection, Marseille, France. Hospital Clínico San Carlos, Madrid, Spain. 186Service de Médecine sity, Samsun, Turkey. 73Necmettin Erbakan University, Meram 125 Department of Paediatrics and Adolescent Medicine, The Intensive Réanimation, Institut de Cardiologie, Hopital Pitié- Medical Faculty, Division of Pediatric Allergy and Immunology, University of Hong Kong, Hong Kong, China. 126National Centre for Salpêtrière, Paris, France. 187CHRU de Nancy, Hôpital d’Enfants, Konya, Turkey. 74Centre Hospitalier Fleyriat, Bourg-en-Bresse, Infectious Diseases, Singapore. 127Hospital Universitario Reina Vandoeuvre, France. 188Chair of Nephrology, University of Brescia, France. 75Division of Clinical Immunology and Allergy, Department Sofía, Cordoba, Spain. 128Imperial College, London, UK. 129Endo- Brescia, Italy. 189Department of Immunology, 2nd Faculty of of Internal Medicine, Necmettin Erbakan University, Meram Medical crinology and Diabetes for Children, AP-HP, Bicêtre Paris-Saclay Medicine, Charles University and Motol University Hospital, Prague, Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 11 of 13 RES EARCH | R E S E A R C H A R T I C L E Czech Republic. 190Clínica Universidad de Navarra, Madrid, Spain. François Téoulé8, Olivier Terrier10, Jean-François Timsit4, Menno D. de Jong12, Rutger Koning4, Niels van Mourik2, 191 HUS Helsinki University Hospital, Children and Adolescents, Rare Théo Trioux4, Christelle Tual33, Sarah Tubiana4, Sylvie van der Werf34, Jeaninne Nellen1, Frederique Paulus2, Edgar Peters1, Tom van der Poll1, Disease Center, and Inflammation Center, Adult Immunodeficiency Noémie Vanel35, Aurélie Veislinger33, Benoit Visseaux16, Benedikt Preckel8, Jan M. Prins1, Jorinde Raasveld2, Tom Reijnders1, Unit, Majakka, Helsinki, Finland. 192Fundació Docència i Recerca Aurélie Wiedemann26, Yazdan Yazdanpanah36 Michiel Schinkel1, Marcus J. Schultz2, Alex Schuurman13, Mútua Terrassa, Terrassa, Spain. 193Department of Pulmonology, Kim Sigaloff1, Marry Smit2, Cornelis S. Stijnis1, Willemke Stilma2, 1 ZNA Middelheim, Antwerp, Belgium. 194INSERM UMR-S 1140, Inserm UMR 1163, Paris, France. 2CHU Amiens, France. 3Hôpital Charlotte Teunissen14, Patrick Thoral2, Anissa Tsonas2, Biosurgical Research Lab (Carpentier Foundation), Paris University Necker, Paris, France. 4Hôpital Bichat, Paris, France. 5Hôpital Louis Marc van der Valk1, Denise Veelo8, Alexander P.J. Vlaar15, and Hopital Européen Georges Pompidou, Paris, France. Mourrier, Colombes, France. 6Institut Pasteur, Paris, France. Heder de Vries2, Michèle van Vugt1, W. Joost Wiersinga1, Dorien Wouters16, 195 7 Department of Pediatrics, Faculty of Medicine, Mansoura F-CRIN Partners Platform, AP-HP, Université de Paris, Paris, A. H. (Koos) Zwinderman17, Diederik van de Beek4* University, Mansoura, Egypt. 196Critical Care Unit, Hospital France. 8Inserm UMR 1136, Paris, France. 9Drugs for Neglected 1 Universitario de Gran Canaria Dr. Negrín, Canarian Health System, Diseases Initiative, Geneva, Switzerland. 10Inserm UMR 1111, Lyon, Department of Infectious Diseases, Amsterdam UMC, Amsterdam, Las Palmas de Gran Canaria, Spain. 197CHU de Saint Etienne, Saint- France. 11Inserm Transfert, Paris, France. 12REACTing, Paris, Netherlands. 2Department of Intensive Care, Amsterdam UMC, Priest-en-Jarez, France. 198Shupyk National Medical Academy for France. 13Inserm UMR 1018, Paris, France. 14Inserm, Pôle Amsterdam, Netherlands. 3Experimental Immunology, Amsterdam Postgraduate Education, Kiev, Ukraine. 199Gustave Roussy Cancer Recherche Clinique, Paris, France. 15CIC 1403 Inserm-CHU Lille, UMC, Amsterdam, Netherlands. 4Department of Neurology, Campus, Villejuif, France. 200Intensive Care Unit, Avicenne Paris, France. 16Université de Paris, IAME, INSERM UMR 1137, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Nether- Hospital, APHP, Bobigny, France. 201Laboratory of Immunology and AP-HP, University Hospital Bichat Claude Bernard, Virology, Paris, lands. 5Department of Pulmonology, Amsterdam UMC, Amsterdam, Histocompatibility, Saint-Louis Hospital, Paris University, Paris, France. 17Inserm UMR 1219, Bordeaux, France. 18ANRS, Paris, Netherlands. 6Department of Infectious Diseases, Amsterdam France. 202Department of Internal Diseases and Pediatrics, Primary France. 19CHU Lille, Lille, France. 20Pasteur Institute, Paris, France. UMC, Amsterdam, Netherlands. 7Department of Pathology, Immune Deficiency Research Lab, Centre for Primary Immuno- 21 Inserm sponsor, Paris, France. 22CHU Rouen–SMIT, Rouen, Amsterdam UMC, Amsterdam, Netherlands. 8Department of deficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, France. 23FCRIN INI-CRCT, Nancy, France. 24Inserm UMR 1137, Anesthesiology, Amsterdam UMC, Amsterdam, Netherlands. 9 Ghent University Hospital, Ghent, Belgium. 203Department of Paris, France. 25Centre d’Investigation Clinique, Inserm CIC1426, Department of Experimental Immunology, Amsterdam UMC, Internal Medicine, Université de Paris, INSERM, U970, PARCC, Hôpital Robert Debré, Paris, France. 26Inserm UMR 955, Créteil, Amsterdam, Netherlands. 10Amsterdam UMC Biobank Core Facility, F-75015, Paris, France. 204First Division of Anesthesiology and France; Vaccine Research Instiute (VRI), Paris, France. 27F-CRIN Amsterdam UMC, Amsterdam, Netherlands. 11Department of Critical Care Medicine, University of Brescia, ASST Spedali Civili di INI-CRCT, Paris, France. 28CHU de Bordeaux–SMIT, Bordeaux, Radiology, Amsterdam UMC, Amsterdam, Netherlands. 12 Brescia, Brescia, Italy. 205Intensive Care Department, Hospital France. 29RENARCI, Annecy, France. 30Hôpital Robert Debré, Paris, Department of Medical Microbiology, Amsterdam UMC, Amster- Universitari Mutua Terrassa, Universitat Barcelona, Terrassa, France. 31Hôpital Louis Mourier–Gynécologie, Colombes, France. dam, Netherlands. 13Department of Internal Medicine, Amsterdam Spain. 206Hospices Civils de Lyon, Lyon Sud Hospital, Lyon, France. 32 University of Lorraine, Plurithematic Clinical Investigation Centre UMC, Amsterdam, Netherlands. 14Neurochemical Laboratory, 207 Infanta Leonor University Hospital, Madrid, Spain. 208Hematol- Inserm CIC-P; 1433, Inserm U1116, CHRU Nancy Hopitaux de Amsterdam UMC, Amsterdam, Netherlands. 15Department of Inten- ogy Department, ASST Spedali Civili di Brescia, Brescia, Italy. Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical sive Care, Amsterdam UMC, Amsterdam, Netherlands. 16Department 209 Pneumologie, Hôpital Avicenne, APHP, INSERM U1272, Uni- Trialists), Nancy, France. 33Inserm CIC-1414, Rennes, France. of Clinical Chemistry, Amsterdam UMC, Amsterdam, Netherlands. 34 17 versité Sorbonne Paris Nord, Bobigny, France. 210Dermatology Institut Pasteur, UMR 3569 CNRS, Université de Paris, Paris, Department of Clinical Epidemiology, Biostatistics and Bio- Unit, Laboratoire GAD, INSERM UMR1231 LNC, Université de France. 35Hôpital la Timone, Marseille, France. 36Bichat–SMIT, informatics, Amsterdam UMC, Amsterdam, Netherlands. 18Depart- Bourgogne, Dijon, France. 211University Hospital of Burgos, Burgos, Paris, France. ment of Neurology, Amsterdam UMC, Amsterdam, Netherlands. Spain. 212Intensive Care Unit, M. Middelares Ghent, Ghent, Belgium. *Leader of the AMC Consortium. 213 Department of Nephrology and Infectiology, AZ Sint-Jan Brugge- CoV-Contact Cohort Loubna Alavoine1, Karine K. A. Amat2, Sylvie Oostende AV, Bruges, Belgium. 214Center of Human Genetics, Behillil3, Julia Bielicki4, Patricia Bruijning5, Charles Burdet6, COVID Human Genetic Effort Laurent Abel1, Alessandro Aiuti2, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. Eric Caumes7, Charlotte Charpentier8, Bruno Coignard9, Saleh Al Muhsen3, Fahd Al-Mulla4, Mark S. Anderson5, 215 Department of Chest Diseases, Necmettin Erbakan University, Yolande Costa1, Sandrine Couffin-Cadiergues10, Florence Damond8, Andrés Augusto Arias6, Hagit Baris Feldman7, Dusan Bogunovic8, Meram Medical Faculty, Konya, Turkey. 216CHU de Caen, Caen, Aline Dechanet11, Christelle Delmas10, Diane Descamps8, Alexandre Bolze9, Anastasiia Bondarenko10, Ahmed A. Bousfiha11, France. 217Sorbonne Université, Service de Médecine Intensive Xavier Duval1, Jean-Luc Ecobichon1, Vincent Enouf3, Hélène Espérou10, Petter Brodin12, Yenan Bryceson12, Carlos D. Bustamante13, Réanimation, Hôpital Tenon, Assistance Publique-Hôpitaux de Wahiba Frezouls1, Nadhira Houhou11, Emila Ilic-Habensus1, Manish Butte14, Giorgio Casari15, Samya Chakravorty16, Downloaded from https://www.science.org on March 04, 2022 Paris, Paris, France. 218General Intensive Care Unit, Konya Training Ouifiya Kafif11, John Kikoine11, Quentin Le Hingrat8, David Lebeaux12, John Christodoulou17, Elizabeth Cirulli9, Antonio Condino-Neto18, and Research Hospital, Konya, Turkey. 219CHU de Nancy, Nancy, Anne Leclercq1, Jonathan Lehacaut1, Sophie Letrou1, Bruno Lina13, Megan A. Cooper19, Clifton L. Dalgard20, Alessia David21, France. 220University of Lyon, CIRI, INSERM U1111, National Referee Jean-Christophe Lucet14, Denis Malvy15, Pauline Manchon11, Joseph L. DeRisi22, Murkesh Desai23, Beth A. Drolet24, Sara Espinosa25, Centre RAISE, Pediatric Rheumatology, HFME, Hospices Civils de Milica Mandic1, Mohamed Meghadecha16, Justina Motiejunaite17, Jacques Fellay26, Carlos Flores27, Jose Luis Franco28, Lyon, Lyon, France. Mariama Nouroudine1, Valentine Piquard11, Andreea Postolache11, Peter K. Gregersen29, Filomeen Haerynck30, David Hagin31, *Leader of COVID Clinicians. Caroline Quintin1, Jade Rexach1, Layidé Roufai10, Zaven Terzian11, Rabih Halwani32, Jim Heath33, Sarah E. Henrickson34, Elena Hsieh35, Michael Thy18, Sarah Tubiana1, Sylvie van der Werf3, Kohsuke Imai36, Yuval Itan8, Timokratis Karamitros37, Kai Kisand38, Imagine COVID Group Christine Bole-Feysot, Stanislas Lyonnet*, Valérie Vignali1, Benoit Visseaux8, Yazdan Yazdanpanah14 Cheng-Lung Ku39, Yu-Lung Lau40, Yun Ling41, Carrie L. Lucas42, Cécile Masson, Patrick Nitschke, Aurore Pouliet, Yoann Schmitt, Tom Maniatis43, Davoud Mansouri44, Laszlo Marodi45, Isabelle Frederic Tores, Mohammed Zarhrate 1 Centre d’Investigation Clinique, Inserm CIC 1425, Hôpital Bichat Meyts46, Joshua Milner47, Kristina Mironska48, Trine Mogensen49, Claude Bernard, APHP, Paris, France. 2IMEA Fondation Léon M’Ba, Tomohiro Morio50, Lisa FP. Ng51, Luigi D. Notarangelo52, Imagine Institute, Université de Paris, INSERM UMR 1163, Paris, Paris, France. 3Institut Pasteur, UMR 3569 CNRS, Université de Antonio Novelli53, Giuseppe Novelli54, Cliona O’Farrelly55, France. Paris, Paris, France. 4University of Basel Children’s Hospital. Satoshi Okada56, Tayfun Ozcelik57, Rebeca Perez de Diego58, *Leader of the Imagine COVID Group. 5 Julius Center for Health Sciences and Primary Care, Utrecht, Anna M. Planas59, Carolina Prando60, Aurora Pujol61, Netherlands. 6Université de Paris, IAME, Inserm UMR 1137, Lluis Quintana-Murci62, Laurent Renia63, Alessandra Renieri64, French COVID Cohort Study Group Laurent Abel1, Claire Andrejak2, F-75018, Paris, France, Hôpital Bichat Claude Bernard, APHP, Carlos Rodríguez-Gallego65, Vanessa Sancho-Shimizu66, François Angoulvant3, Delphine Bachelet4, Romain Basmaci5, Paris, France. 7Hôpital Pitiè Salpétriere, APHP, Paris. 8Université de Vijay Sankaran67, Kelly Schiabor Barrett9, Mohammed Shahrooei68, Sylvie Behillil6, Marine Beluze7, Dehbia Benkerrou8, Krishna Bhavsar4, Paris, IAME, INSERM UMR 1137, AP-HP, University Hospital Bichat Andrew Snow69, Pere Soler-Palacín70, András N. Spaan71, François Bompart9, Lila Bouadma4, Maude Bouscambert10, Claude Bernard, Virology, Paris, France. 9Santé Publique France, Stuart Tangye72, Stuart Turvey73, Furkan Uddin74, Mireille Caralp11, Minerva Cervantes-Gonzalez12, Anissa Chair4, Saint Maurice, France. 10Pole Recherche Clinique, Inserm, Paris, Mohammed J. Uddin75, Diederik van de Beek76, Sara E. Vazquez77, Alexandra Coelho13, Camille Couffignal4, Sandrine Couffin-Cadiergues14, France. 11Hôpital Bichat Claude Bernard, APHP, Paris, France. Donald C. Vinh78, Horst von Bernuth79, Nicole Washington9, Eric D’Ortenzio12, Charlene Da Silveira4, Marie-Pierre Debray4, 12 APHP, Paris, France. 13Virpath Laboratory, International Center of Pawel Zawadzki80, Helen C. Su52, Jean-Laurent Casanova81 Dominique Deplanque15, Diane Descamps16, Mathilde Desvallées17, Research in Infectiology, Lyon University, INSERM U1111, CNRS Alpha Diallo18, Alphonsine Diouf13, Céline Dorival8, François Dubos19, UMR 5308, ENS, UCBL, Lyon, France. 14IAME Inserm UMR 1138, 1 INSERM U1163, University of Paris, Imagine Institute, Paris, France. Xavier Duval4, Philippine Eloy4, Vincent VE Enouf20, Hôpital Bichat Claude Bernard, APHP, Paris, France. 15Service des 2 San Raffaele Telethon Institute for Gene Therapy, IRCCS Ospedale Hélène Esperou21, Marina Esposito-Farese4, Manuel Etienne22, Maladies Infectieuses et Tropicales; Groupe Pellegrin-Place Amélie- San Raffaele, Milan, Italy. 3King Saud University, Riyadh, Saudi Nadia Ettalhaoui4, Nathalie Gault4, Alexandre Gaymard10, Raba-Léon, Bordeaux, France. 16Hôpital Hotel Dieu, APHP, Paris, Arabia. 4Kuwait University, Kuwait City, Kuwait. 5University of Jade Ghosn4, Tristan Gigante23, Isabelle Gorenne4, Jérémie Guedj24, France. 17Service des Explorations Fonctionnelles, Hôpital Bichat– California, San Francisco, San Francisco, CA, USA. 6Universidad de Alexandre Hoctin13, Isabelle Hoffmann4, Salma Jaafoura21, Claude Bernard, APHP, Paris, France. 18Center for Clinical Antioquia, Group of Primary Immunodeficiencies, Antioquia, Colom- Ouifiya Kafif4, Florentia Kaguelidou25, Sabina Kali4, Antoine Khalil4, Investigation, Assistance Publique-Hôpitaux de Paris, Bichat- bia. 7The Genetics Institute, Tel Aviv Sourasky Medical Center and Coralie Khan17, Cédric Laouénan4, Samira Laribi4, Minh Le4, Claude Bernard University Hospital, Paris, France. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Quentin Le Hingrat4, Soizic Le Mestre18, Hervé Le Nagard24, 8 Icahn School of Medicine at Mount Sinai, New York, NY, USA. 9Helix, François-Xavier Lescure4, Yves Lévy26, Claire Levy-Marchal27, Amsterdam UMC Covid-19 Biobank Michiel van Agtmael1, San Mateo, CA, USA. 10Shupyk National Medical Academy for Bruno Lina10, Guillaume Lingas24, Jean Christophe Lucet4, Denis Malvy28, Anna Geke Algera2, Frank van Baarle2, Diane Bax3, Martijn Beudel4, Postgraduate Education, Kiev, Ukraine. 11Clinical Immunology Unit, Marina Mambert13, France Mentré4, Noémie Mercier18, Amina Meziane8, Harm Jan Bogaard5, Marije Bomers1, Lieuwe Bos2, Michela Botta2, Pediatric Infectious Disease Departement, Faculty of Medicine and Hugo Mouquet20, Jimmy Mullaert4, Nadège Neant24, Marion Noret29, Justin de Brabander6, Godelieve de Bree6, Matthijs C. Brouwer4, Pharmacy, Averroes University Hospital; LICIA Laboratoire d’Immu- Justine Pages30, Aurélie Papadopoulos21, Christelle Paul18, Sanne de Bruin2, Marianna Bugiani7, Esther Bulle2, Osoul Chouchane1, nologie Clinique, d’Inflammation et d’Allergie, Hassann Ii University, Nathan Peiffer-Smadja4, Ventzislava Petrov-Sanchez18, Gilles Peytavin4, Alex Cloherty3, Paul Elbers2, Lucas Fleuren2, Suzanne Geerlings1, Casablanca, Morocco. 12Karolinska Institute, Stockholm, Sweden. Olivier Picone31, Oriane Puéchal12, Manuel Rosa-Calatrava10, Bart Geerts8, Theo Geijtenbeek9, Armand Girbes2, Bram Goorhuis1, 13 Stanford University, Stanford, CA, USA. 14University of California, Bénédicte Rossignol23, Patrick Rossignol32, Carine Roy4, Martin P. Grobusch1, Florianne Hafkamp9, Laura Hagens2, Los Angeles, CA, USA. 15Medical Genetics, IRCCS Ospedale San Marion Schneider4, Caroline Semaille12, Nassima Si Mohammed4, Jorg Hamann10, Vanessa Harris1, Robert Hemke11, Sabine M. Hermans1, Raffaele, Milan, Italy. 16Emory University Department of Pediatrics Lysa Tagherset4, Coralie Tardivon4, Marie-Capucine Tellier4, Leo Heunks2, Markus W. Hollmann8, Janneke Horn2, Joppe W. Hovius1, and Children’s Healthcare of Atlanta, Atlanta, GA, USA. 17Murdoch Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 12 of 13 RES EARCH | R E S E A R C H A R T I C L E Children’s Research Institute, Victoria, Australia. 18University of São Hospital, Rome, Italy. 54Department of Biomedicine and Prevention, 81 Rockefeller University, Howard Hughes Medical Institute, Necker Paulo, São Paulo, Brazil. 19Washington University School of Medicine, University of Rome “Tor Vergata,” Rome, Italy. 55Trinity College, Hospital, New York, NY, USA. St. Louis, MO, USA. 20The American Genome Center; Uniformed Dublin, Ireland. 56Hiroshima University, Hiroshima, Japan. *Leaders of the COVID Human Genetic Effort. 57 Services University of the Health Sciences, Bethesda, MD, USA. Bilkent University, Ankara, Turkey. 58Laboratory of Immuno- 21 Centre for Bioinformatics and System Biology, Department of Life genetics of Human Diseases, Innate Immunity Group, IdiPAZ NIAID-USUHS/TAGC COVID Immunity Group Huie Jing1,2, Sciences, Imperial College London, South Kensington Campus, Institute for Health Research, La Paz Hospital, Madrid, Spain. Wesley Tung1,2, Christopher R. Luthers3, Bradly M. Bauman3, London, UK. 22University of California, San Francisco, CA, USA; Chan 59 IIBB-CSIC, IDIBAPS, Barcelona, Spain. 60Faculdades Pequeno Samantha Shafer2,4, Lixin Zheng2,4, Zinan Zhang2,4, Zuckerberg Biohub, San Francisco, CA, USA. 23Bai Jerbai Wadia Príncipe e Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Satoshi Kubo2,4, Samuel D. Chauvin2,4, Kazuyuki Meguro1,2, Hospital for Children, Mumbai, India. 24School of Medicine and Public Brazil. 61Neurometabolic Diseases Laboratory, IDIBELL–Hospital Elana Shaw1,2, Michael Lenardo2,4, Justin Lack5, Eric Karlins6, Health, University of Wisconsin, Madison, WI, USA. 25Instituto Duran I Reynals; Catalan Institution for Research and Advanced Daniel M. Hupalo7, John Rosenberger7, Gauthaman Sukumar7, Nacional de Pediatria (National Institute of Pediatrics), Mexico City, Studies (ICREA); CIBERER U759, ISCiii Madrid Spain, Barcelona, Matthew D. Wilkerson7, Xijun Zhang7 Mexico. 26Swiss Federal Institute of Technology Lausanne, Lau- Spain. 62Institut Pasteur (CNRS UMR2000) and Collège de France, 1 Laboratory of Clinical Immunology and Microbiology, Division of sanne, Switzerland. 27Research Unit, Hospital Universitario Nuestra Paris, France. 63Infectious Diseases Horizontal Technology Center Intramural Research, NIAID, NIH, Bethesda, MD, USA. 2NIAID Señora de Candelaria, Canarian Health System, Santa Cruz de and Singapore Immunology Network, Agency for Science Tech- Clinical Genomics Program, National Institutes of Health, Bethesda, Tenerife, Spain. 28University of Antioquia, Medellín, Colombia. nology (A*STAR), Singapore. 64Medical Genetics, University of MD, USA. 3Department of Pharmacology & Molecular Therapeutics, 29 Feinstein Institute for Medical Research, Northwell Health USA, Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Uniformed Services University of the Health Sciences, Bethesda, Manhasset, NY, USA. 30Department of Paediatric Immunology and Senese, Italy; GEN-COVID Multicenter Study. 65Hospital Universitario MD, USA. 4Laboratory of Immune System Biology, Division of Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), de Gran Canaria Dr. Negrín, Canarian Health System, Canary Intramural Research, NIAID, NIH, Bethesda, MD, USA. 5NIAID PID Research Lab, Jeffrey Modell Diagnosis and Research Centre, Islands, Spain. 66Imperial College London, London, UK. 67Boston Collaborative Bioinformatics Resource, Frederick National Labora- Ghent University Hospital, Edegem, Belgium. 31The Genetics Children’s Hospital, Harvard Medical School, Boston, MA, USA. tory for Cancer Research, Leidos Biomedical Research, Inc., Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 32Sharjah 68 Saeed Pathobiology and Genetic Lab, Tehran, Iran. 69Uniformed Frederick, MD, USA. 6Bioinformatics and Computational Biosciences Institute of Medical Research, College of Medicine, University of Services University of the Health Sciences, Bethesda, MD, USA. Branch, Office of Cyber Infrastructure and Computational Sharjah, Sharjah, UAE. 33Institute for Systems Biology, Seattle, WA, 70 Hospital Universitari Vall d’Hebron, Barcelona, Spain. 71Univer- Biology, NIAID, NIH, Bethesda, MD, USA. 7The American Genome USA. 34Children’s Hospital of Philadelphia, Philadelphia, PA, USA. sity Medical Center Utrecht, Amsterdam, The Netherlands. Center, Uniformed Services University of the Health Sciences, 35 Anschutz Medical Campus, Aurora, CO, USA. 36Riken, Tokyo, 72 Garvan Institute of Medical Research, Sydney, Australia. Bethesda, MD, USA. Japan. 37Hellenic Pasteur Institute, Athens, Greece. 38University of 73 The University of British Columbia, Vancouver, Canada. 74Holy Tartu, Tartu, Estonia. 39Chang Gung University, Taoyuan County, Family Red Crescent Medical College; Centre for Precision Taiwan. 40The University of Hong Kong, Hong Kong, China. Therapeutics, NeuroGen Children’s Healthcare; Genetics and SUPPLEMENTARY MATERIALS 41 Shanghai Public Health Clinical Center, Fudan University, Shanghai, Genomic Medicine Centre, NeuroGen Children’s Healthcare, science.sciencemag.org/content/370/6515/eabd4570/suppl/DC1 China. 42Yale School of Medicine, New Haven, CT, USA. 43New York Dhaka, Bangladesh. 75Mohammed Bin Rashid University of Materials and Methods Genome Center, New York, NY, USA. 44Shahid Beheshti University of Medicine and Health Sciences, College of Medicine, Dubai, UAE; Figs. S1 to S11 Medical Sciences, Tehran, Iran. 45Semmelweis University Budapest, The Centre for Applied Genomics, Department of Genetics and Tables S1 and S2 Budapest, Hungary. 46KU Leuven, Department of Immunology, Genome Biology, The Hospital for Sick Children, Toronto, Ontario, References (42 and 43) Microbiology and Transplantation, Leuven, Belgium. 47Columbia Canada. 76Amsterdam UMC, University of Amsterdam, MDAR Reproducibility Checklist University Medical Center, New York, NY, USA. 48University Clinic for Department of Neurology, Amsterdam Neuroscience, Amsterdam, Children’s Diseases, Skopje, North Macedonia. 49Aarhus University, The Netherlands. 77University of California, San Francisco, CA, View/request a protocol for this paper from Bio-protocol. Aarhus, Denmark. 50Tokyo Medical & Dental University Hospital, USA. 78McGill University Health Centre, Montreal, Canada. Tokyo, Japan. 51Singapore Immunology Network, Singapore. 79 Charité–Berlin University Hospital Center, Berlin, Germany. 22 June 2020; accepted 16 September 2020 52 80 National Institute of Allergy and Infectious Diseases, National Molecular Biophysics Division, Faculty of Physics, A. Mickiewicz Published online 24 September 2020 Institutes of Health, Bethesda, MD, USA. 53Bambino Gesù Children’s University, Uniwersytetu Poznanskiego 2, Poznań, Poland. 10.1126/science.abd4570 Downloaded from https://www.science.org on March 04, 2022 Zhang et al., Science 370, eabd4570 (2020) 23 October 2020 13 of 13 Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 Qian ZhangPaul BastardZhiyong LiuJérémie Le PenMarcela Moncada-VelezJie ChenMasato OgishiIra K. D. SabliStephanie HodeibCecilia KorolJérémie RosainKaya BilguvarJunqiang YeAlexandre BolzeBenedetta BigioRui YangAndrés Augusto AriasQinhua ZhouYu ZhangFanny OnodiSarantis KorniotisLéa KarpfQuentin PhilippotMarwa ChbihiLucie Bonnet-MadinKarim DorghamNikaïa SmithWilliam M. SchneiderBrandon S. RazookyHans-Heinrich HoffmannEleftherios MichailidisLeen MoensJi Eun HanLazaro LorenzoLucy BizienPhilip MeadeAnna-Lena NeehusAileen Camille UgurbilAurélien CorneauGaspard KernerPeng ZhangFranck RapaportYoann SeeleuthnerJeremy ManryCecile MassonYohann SchmittAgatha SchlüterTom Le VoyerTaushif KhanJuan LiJacques FellayLucie RousselMohammad ShahrooeiMohammed F. AlosaimiDavood MansouriHaya Al-SaudFahd Al-MullaFeras AlmourfiSaleh Zaid Al- MuhsenFahad AlsohimeSaeed Al TurkiRana HasanatoDiederik van de BeekAndrea BiondiLaura Rachele BettiniMariella D’Angio’Paolo BonfantiLuisa ImbertiAlessandra SottiniSimone PagheraEugenia Quiros-RoldanCamillo RossiAndrew J. OlerMiranda F. TompkinsCamille AlbaIsabelle VandernootJean-Christophe GoffardGuillaume SmitsIsabelle MigeotteFilomeen HaerynckPere Soler-PalacinAndrea Martin-NaldaRoger ColobranPierre-Emmanuel MorangeSevgi KelesFatma ÇölkesenTayfun OzcelikKadriye Kart YasarSevtap Senoglu#emsi Nur KarabelaCarlos Rodríguez- GallegoGiuseppe NovelliSami HraiechYacine Tandjaoui-LambiotteXavier DuvalCédric LaouénanAndrew L. SnowClifton L. DalgardJoshua D. MilnerDonald C. VinhTrine H. MogensenNico MarrAndrás N. SpaanBertrand BoissonStéphanie Boisson-DupuisJacinta BustamanteAnne PuelMichael J. CiancanelliIsabelle MeytsTom ManiatisVassili SoumelisAli AmaraMichel NussenzweigAdolfo García-SastreFlorian KrammerAurora PujolDarragh DuffyRichard P. LiftonShen-Ying ZhangGuy GorochovVivien BéziatEmmanuelle JouanguyVanessa Sancho-ShimizuCharles M. RiceLaurent AbelLuigi D. NotarangeloAurélie CobatHelen C. SuJean-Laurent Casanova, and Giuseppe Foti, and Giacomo Bellani, and Giuseppe Citerio, and Ernesto Contro, and Alberto Pesci, and Maria Grazia Valsecchi, and Marina Cazzaniga, 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 Barrou, and Alexandra Beurton, and Agurtzane Bilbao, and Geraldine Blanchard- Downloaded from https://www.science.org on March 04, 2022 Rohner, and Ignacio Blanco, and Adeline Blandinières, and Daniel Blazquez-Gamero, and Marketa Bloomfield, and Mireia Bolivar-Prados, and Raphael Borie, and Cédric Bosteels, 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 Çölkesen, and Roger Colobran, and Cloé Comarmond, 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 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 Mònica 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 Cathérine Heijmans, and María Soledad Holanda-Peña, and Juan Pablo Horcajada, and Levi Hoste, and Eric Hoste, 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 Philippe Jorens, 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 Bart N. Lambrecht, 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 Bart Loeys, 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 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 Antonio Morales Martinez, and Pierre Morange, and Clémence Mordacq, and Guillaume Morelle, and Stéphane Mouly, and Adrián Muñoz-Barrera, and Leslie Naesens, 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 Sandra Pellegrini, 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 Hans Slabbynck, and David M. 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 Eva Van Braeckel, and Stijn Van de Velde, and Ana Maria Van Den Rym, and Jens Van Praet, 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 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, and Alphonsine Downloaded from https://www.science.org on March 04, 2022 Diouf, and Céline Dorival, and François Dubos, and Xavier Duval, and Philippine Eloy, and Vincent VE 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 Trioux, 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 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, 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 de Bree, and Matthijs C. Brouwer, and Sanne de Bruin, and Marianna Bugiani, and Esther Bulle, and O. 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, 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 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 Alessia David, 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 Milner, and Kristina Mironska, and Trine Mogensen, and Tomohiro Morio, and Lisa F. P. Ng, and Luigi D. Notarangelo, and Antonio Novelli, and Giuseppe 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 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, and Huie Jing, and Wesley Tung, and Christopher R. Luthers, and Bradly M. Bauman, and Samantha Shafer, and Lixin Zheng, and Zinan Zhang, and Satoshi Kubo, and Samuel D. Chauvin, and Kazuyuki Meguro, and Elana Shaw, and Michael Lenardo, and Justin Lack, and Eric Karlins, and Daniel M. Hupalo, and John Rosenberger, and Gauthaman Sukumar, and Matthew D. Wilkerson, and Downloaded from https://www.science.org on March 04, 2022 Xijun Zhang Science, 370 (6515), eabd4570. • DOI: 10.1126/science.abd4570 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 et al. used a candidate gene 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 et al. identified individuals with high titers of neutralizing autoantibodies against 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.abd4570 Permissions https://www.science.org/help/reprints-and-permissions Downloaded from https://www.science.org on March 04, 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