Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Publication date
2020-10-23
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
Editors
Advisors
Supervisors
Document Type
Article
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cc_by
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.
Keywords
Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, COVID-19, Child, Child, Preschool, Coronavirus Infections/genetics, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7/deficiency, Interferon Type I/immunology, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral/genetics, Receptor, Interferon alpha-beta/deficiency, SARS-CoV-2, Toll-Like Receptor 3/deficiency, Young Adult, General, Research Support, Non-U.S. Gov't, Journal Article
Citation
Zhang, Q, Bastard, P, Liu, Z, Le Pen, J, Moncada-Velez, M, Chen, J, Ogishi, M, Sabli, I K D, Hodeib, S, Korol, C, Rosain, J, Bilguvar, K, Ye, J, Bolze, A, Bigio, B, Yang, R, Arias, A A, Zhou, Q, Zhang, Y, Onodi, F, Korniotis, S, Karpf, L, Philippot, Q, Chbihi, M, Bonnet-Madin, L, Dorgham, K, Smith, N, Schneider, W M, Razooky, B S, Hoffmann, H-H, Michailidis, E, Moens, L, Han, J E, Lorenzo, L, Bizien, L, Meade, P, Neehus, A-L, Ugurbil, A C, Corneau, A, Kerner, G, Zhang, P, Rapaport, F, Seeleuthner, Y, Manry, J, Masson, C, Schmitt, Y, Schlüter, A, Le Voyer, T, Khan, T, Spaan, A N, COVID-STORM Clinicians & Bruijning-Verhagen, P 2020, 'Inborn errors of type I IFN immunity in patients with life-threatening COVID-19', Science, vol. 370, no. 6515, eabd4570. https://doi.org/10.1126/science.abd4570