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EP News: Basic and Translational

Published:November 09, 2020DOI:https://doi.org/10.1016/j.hrthm.2020.11.006
      One of the most perplexing features of coronavirus disease 2019 (COVID-19) is the fact that the disease can range from silent infection to lethal outcome in different individuals. In the current study, Zhang et al (Science 2020;370(6515):eabd4570; PMID: 32972995) demonstrate an enrichment in rare variants predicted to be loss-of-function (LOF) at 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. The IFN-I family includes IFN-α, IFN-β and IFN-ω. These molecules provide innate immune defenses. The authors sequence the exome or genome from 659 patients with life-threatening COVID-19 pneumonia, relative to subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, the authors define LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) carrying 24 deleterious variants of eight genes. The authors demonstrate that human fibroblasts with mutations affecting this circuit are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The authors conclude that 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.
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