Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Qian Zhang 1, Paul Bastard # 2 3, Zhiyong Liu # 1, Jérémie Le Pen # 4, Marcela Moncada-Velez # 1, Jie Chen # 1, Masato Ogishi # 1, Ira K D Sabli # 5, Stephanie Hodeib # 5, Cecilia Korol # 2, Jérémie Rosain # 2 3, Kaya Bilguvar # 6, Junqiang Ye # 7, Alexandre Bolze # 8, Benedetta Bigio # 1, Rui Yang # 1, Andrés Augusto Arias # 1 9 10, Qinhua Zhou # 1, Yu Zhang # 11 12, Fanny Onodi 13, Sarantis Korniotis 13, Léa Karpf 13, Quentin Philippot 2 3, Marwa Chbihi 2 3, Lucie Bonnet-Madin 14, Karim Dorgham 15, Nikaïa Smith 16, William M Schneider 4, Brandon S Razooky 4, Hans-Heinrich Hoffmann 4, Eleftherios Michailidis 4, Leen Moens 17, Ji Eun Han 1, Lazaro Lorenzo 2 3, Lucy Bizien 2 3, Philip Meade 18, Anna-Lena Neehus 2 3, Aileen Camille Ugurbil 1, Aurélien Corneau 19, Gaspard Kerner 2 3, Peng Zhang 1, Franck Rapaport 1, Yoann Seeleuthner 2 3, Jeremy Manry 2 3, Cecile Masson 20, Yohann Schmitt 20, Agatha Schlüter 21, Tom Le Voyer 2 3, Taushif Khan 22, Juan Li 1, Jacques Fellay 23 24 25, Lucie Roussel 26, Mohammad Shahrooei 27 28, Mohammed F Alosaimi 29, Davood Mansouri 30 31 32, Haya Al-Saud 33, Fahd Al-Mulla 34, Feras Almourfi 33, Saleh Zaid Al-Muhsen 35, Fahad Alsohime 29, Saeed Al Turki 36 37, Rana Hasanato 29, Diederik van de Beek 38, Andrea Biondi 39, Laura Rachele Bettini 39, Mariella D'Angio' 39, Paolo Bonfanti 40, Luisa Imberti 41, Alessandra Sottini 41, Simone Paghera 41, Eugenia Quiros-Roldan 42, Camillo Rossi 43, Andrew J Oler 44, Miranda F Tompkins 45, Camille Alba 45, Isabelle Vandernoot 46, Jean-Christophe Goffard 47, Guillaume Smits 46, Isabelle Migeotte 48, Filomeen Haerynck 49, Pere Soler-Palacin 50, Andrea Martin-Nalda 50, Roger Colobran 51, Pierre-Emmanuel Morange 52, Sevgi Keles 53, Fatma Çölkesen 54, Tayfun Ozcelik 55, Kadriye Kart Yasar 56, Sevtap Senoglu 56, Şemsi Nur Karabela 56, Carlos Rodríguez-Gallego 57 58, Giuseppe Novelli 59, Sami Hraiech 60, Yacine Tandjaoui-Lambiotte 61 62, Xavier Duval 63 64, Cédric Laouénan 63 64 65; COVID-STORM Clinicians; COVID Clinicians; Imagine COVID Group; French COVID Cohort Study Group; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; NIAID-USUHS/TAGC COVID Immunity Group; Andrew L Snow 66, Clifton L Dalgard 45 67, Joshua D Milner 68, Donald C Vinh 26, Trine H Mogensen 69 70, Nico Marr 22 71, András N Spaan 1 72, Bertrand Boisson 1 2 3, Stéphanie Boisson-Dupuis 1 2 3, Jacinta Bustamante 1 2 3 73, Anne Puel 1 2 3, Michael J Ciancanelli 1 74, Isabelle Meyts 17 75, Tom Maniatis 7 76, Vassili Soumelis 13 77, Ali Amara 14, Michel Nussenzweig 78 79, Adolfo García-Sastre 18 80 81 82, Florian Krammer 18, Aurora Pujol 21, Darragh Duffy 16, Richard P Lifton # 83 84 85, Shen-Ying Zhang # 1 2 3, Guy Gorochov # 15, Vivien Béziat # 1 2 3, Emmanuelle Jouanguy # 1 2 3, Vanessa Sancho-Shimizu # 5, Charles M Rice # 4, Laurent Abel # 1 2 3, Luigi D Notarangelo # 11 12, Aurélie Cobat # 1 2 3, Helen C Su # 11 12, Jean-Laurent Casanova # 86 2 3 79 87
Affiliations
Affiliations
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
- University of Paris, Imagine Institute, Paris, France.
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
- Department of Paediatric Infectious Diseases & Virology, Imperial College London, London, UK.
- Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
- Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
- Helix, San Mateo, CA, USA.
- Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia.
- School of Microbiology, University of Antioquia UdeA, Medellin, Colombia.
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
- NIAID Clinical Genomics Program, NIH, Bethesda, MD, USA.
- Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, Paris, France.
- Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR 7212, Université de Paris, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France.
- Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (CIMI PARIS), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Pitié-Salpêtrière, Paris, France.
- Translational Immunology Lab, Institut Pasteur, Paris, France.
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
- Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
- Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
- Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
- School of Life sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
- Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
- Swiss Institue of Bioinformatics, Lausanne, Switzerland.
- Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada.
- Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
- Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium.
- Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
- Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- The 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.
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti, Iran.
- National Center of Genomics Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
- Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Kuwait.
- Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
- Translational Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Misery of National Guard Health Affairs, Riyadh, Saudi Arabia.
- Cancer & Blood Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
- Amsterdam UMC, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands.
- Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
- Department of Infectious Diseases, San Gerardo Hospital-University of Milano-Bicocca, Monza, Italy.
- CREA Laboratory, Diagnostic Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy.
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy.
- Chief Medical Officer, ASST Spedali Civili di Brescia, Brescia, Italy.
- Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA.
- PRIMER, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
- Department of Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
- Fonds de la Recherche Scientifique (FNRS) and Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
- Department 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.
- Pediatric 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.
- Immunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain.
- Aix Marseille Univ, INSERM, INRAE, C2VN, CHU Timone, Marseille, France.
- Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey.
- Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey.
- Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey.
- Departments of Infectious Diseases and Clinical Microbiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
- Department of Immunology, Hospital Universitario de G.C. Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
- University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Rome, Italy.
- Intensive Care Unit, AP-HM, Marseille, France.
- Avicenne Hospital Intensive Care Unit, APHP, Bobigny, INSERM U1272 Hypoxia & Lung, Paris, France.
- PH Réanimation CHU Avicenne, Bobigny, INSERM U1272 Hypoxie & Poumon, Paris, France.
- Université de Paris, IAME UMR-S 1137, INSERM, Paris, France.
- Inserm CIC 1425, Paris, France.
- AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France.
- Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University, New York, USA.
- Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
- Department of Medical Microbiology, Utrecht UMC, Utrecht, Netherlands.
- Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
- Turnstone Biologics, New York, NY, USA.
- Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
- New York Genome Center, New York, NY, USA.
- AP-HP, Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France.
- Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA.
- Howard Hughes Medical Institute, New York, NY, USA.
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA.
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. casanova@rockefeller.edu.
- Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
Abstract
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
References
https://pubmed.ncbi.nlm.nih.gov/