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

Science. 2020 Oct 23;370(6515):eabd4570. doi: 10.1126/science.abd4570. Epub 2020 Sep 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Asymptomatic Infections
  • Betacoronavirus
  • COVID-19
  • Child
  • Child, Preschool
  • Coronavirus Infections / genetics*
  • Coronavirus Infections / immunology*
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Interferon Regulatory Factor-7 / deficiency
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Type I / immunology*
  • Loss of Function Mutation*
  • Male
  • Middle Aged
  • 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

Substances

  • IFNAR1 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Receptor, Interferon alpha-beta

Associated data

  • Dryad/10.5061/dryad.8pk0p2nkk