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


Zhang, Qian ORCID: 0000-0002-9040-3289, Bastard, Paul ORCID: 0000-0002-5926-8437, Liu, Zhiyong ORCID: 0000-0001-6473-348X, Le Pen, Jérémie ORCID: 0000-0001-7025-9526, Moncada-Velez, Marcela ORCID: 0000-0002-3073-5345, Chen, Jie ORCID: 0000-0002-5354-4170, Ogishi, Masato ORCID: 0000-0003-2421-7389, Sabli, Ira KD ORCID: 0000-0002-0170-2990, Hodeib, Stephanie ORCID: 0000-0002-5978-6189, Korol, Cecilia ORCID: 0000-0002-0023-8823 et al (show 128 more authors) (2020) Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science (New York, N.Y.), 370 (6515). eabd4570-.

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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.

Item Type: Article
Uncontrolled Keywords: 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, Humans, Pneumonia, Viral, Coronavirus Infections, Genetic Predisposition to Disease, Interferon Type I, Alleles, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Interferon Regulatory Factor-7, Toll-Like Receptor 3, Receptor, Interferon alpha-beta, Young Adult, Genetic Loci, Asymptomatic Infections, Pandemics, Betacoronavirus, Loss of Function Mutation, COVID-19, SARS-CoV-2
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User: Symplectic Admin
Date Deposited: 26 May 2021 10:30
Last Modified: 11 Feb 2023 02:57
DOI: 10.1126/science.abd4570
Open Access URL: https://science.sciencemag.org/content/370/6515/ea...
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3124105
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