Clinical outcome following infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. In this article recently published in Science, the authors found enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and 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, the authors experimentally defined LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. Moreover, they showed that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. The authors concluded 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.