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; 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

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-α2 and IFN-ω 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 A large immunological and genomics study of COVID-19 patients reveals excess mutations in the type I IFN pathway. 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.