Zhang, QianBastard, PaulLiu, ZhiyongLe Pen, JeremieMoncada-Velez, MarcelaChen, JieOgishi, Masato2024-02-232024-02-2320200036-80751095-9203https://doi.org/10.1126/science.abd4570https://hdl.handle.net/20.500.12452/14066Clinical 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.eninfo:eu-repo/semantics/openAccess[Keyword Not Available]Article3706515329729952-s2.0-85094120212Q1WOS:000581077200034Q110.1126/science.abd4570