Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

• Published in: Science (American Association for the Advancement of Science) Vol. 370; no. 6515
• Main Authors: Zhang, Qian, Bastard, Paul, Liu, Zhiyong, Le Pen, Jérémie, Moncada-Velez, Marcela, Chen, Jie, Ogishi, Masato, Sabli, Ira K D, Hodeib, Stephanie, Korol, Cecilia, Rosain, Jérémie, Bilguvar, Kaya, Ye, Junqiang, Bolze, Alexandre, Bigio, Benedetta, Yang, Rui, Arias, Andrés Augusto, Zhou, Qinhua, Zhang, Yu, Onodi, Fanny, Korniotis, Sarantis, Karpf, Léa, Philippot, Quentin, Chbihi, Marwa, Bonnet-Madin, Lucie, Dorgham, Karim, Smith, Nikaïa, Schneider, William M, Razooky, Brandon S, Hoffmann, Hans-Heinrich, Michailidis, Eleftherios, Moens, Leen, Han, Ji Eun, Lorenzo, Lazaro, Bizien, Lucy, Meade, Philip, Neehus, Anna-Lena, Ugurbil, Aileen Camille, Corneau, Aurélien, Kerner, Gaspard, Zhang, Peng, Rapaport, Franck, Seeleuthner, Yoann, Manry, Jeremy, Masson, Cecile, Schmitt, Yohann, Schlüter, Agatha, Le Voyer, Tom, Khan, Taushif, Li, Juan, Fellay, Jacques, Roussel, Lucie, Shahrooei, Mohammad, Alosaimi, Mohammed F, Mansouri, Davood, Al-Saud, Haya, Al-Mulla, Fahd, Almourfi, Feras, Al-Muhsen, Saleh Zaid, Alsohime, Fahad, Al Turki, Saeed, Hasanato, Rana, van de Beek, Diederik, Biondi, Andrea, Bettini, Laura Rachele, D'Angio', Mariella, Bonfanti, Paolo, Imberti, Luisa, Sottini, Alessandra, Paghera, Simone, Quiros-Roldan, Eugenia, Rossi, Camillo, Oler, Andrew J, Tompkins, Miranda F, Alba, Camille, Vandernoot, Isabelle, Goffard, Jean-Christophe, Smits, Guillaume, Migeotte, Isabelle, Haerynck, Filomeen, Soler-Palacin, Pere, Martin-Nalda, Andrea, Colobran, Roger, Morange, Pierre-Emmanuel, Keles, Sevgi, Çölkesen, Fatma, Ozcelik, Tayfun, Yasar, Kadriye Kart, Senoglu, Sevtap, Karabela, Şemsi Nur, Rodríguez-Gallego, Carlos, Novelli, Giuseppe, Hraiech, Sami, Tandjaoui-Lambiotte, Yacine, Duval, Xavier, Laouénan, Cédric, Snow, Andrew L, Dalgard, Clifton L, Milner, Joshua D, Vinh, Donald C
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 23-10-2020; American Association for the Advancement of Science
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Asymptomatic Infections; Betacoronavirus; Child; Child, Preschool; Coronavirus Infections - genetics; Coronavirus Infections - immunology; COVID-19; Female; Genetic Loci; Genetic Predisposition to Disease; Genetics; Human health and pathology; Humans; Immunology; Infant; Infectious diseases; Interferon Regulatory Factor-7 - deficiency; Interferon Regulatory Factor-7 - genetics; Interferon Type I - immunology; Life Sciences; Loss of Function Mutation; Male; Medicin och hälsovetenskap; Middle Aged; Online; Pandemics; Pneumonia, Viral - genetics; Pneumonia, Viral - immunology; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; SARS-CoV-2; Toll-Like Receptor 3 - deficiency; Toll-Like Receptor 3 - genetics; Young Adult
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abd4570

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.