Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Top Cited Papers
Open Access
- 22 October 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 370 (6515)
- https://doi.org/10.1126/science.abd4570
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
Funding Information
- National Institutes of Health (R01AI088364)
- Howard Hughes Medical Institute
- St. Giles Foundation
- National Center for Advancing Translational Sciences
- Rockefeller University
- French National Research Agency (ANR-10-IAHU-01)
- the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID)
- National Human Genome Research Institute (UM1HG006504 and U24HG008956)
- the French Foundation for Medical Research (EQU201903007798)
- NIH Clinical and Translational Science Award (UL1 TR001866)
- Emergent Ventures (fast grant)
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