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

Abstract

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal 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 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, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway 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.

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

“…31,32 Indeed, 3.5% of patients had known (AR IRF7 and IFNAR1 deficiency, autosomal-dominant TLR3, TICAM1, TBK1, and IRF3 deficiency) and new (autosomal-dominant UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiency) genetic defects abolishing induction or amplification of type I IFNs. 39 In the second study, neutralizing autoantibodies against type I IFNs were found in 10.2% of 987 patients with life-threatening COVID-19 pneumonia, resulting in low or undetectable serum levels of IFN-a during acute disease; 94% of the patients with autoantibodies were male. The net result of both the anti-IFN autoantibodies and the loss-of-function variants in crucial type I IFN pathway genes is a profound defect in type I IFN immunity, underlying life-threatening COVID-19 pneumonia.…”

“…Two recent studies provide convincing evidence that disruption of type I IFN signaling is a frequent cause of life-threatening COVID-19. 39,40 In the first study, 650 patients with lifethreatening COVID-19 were studied by whole-exome sequencing under the hypothesis that severe COVID-19 is allelic with severe influenza 39 or that genes biologically related to these loci would be involved. 31,32 Indeed, 3.5% of patients had known (AR IRF7 and IFNAR1 deficiency, autosomal-dominant TLR3, TICAM1, TBK1, and IRF3 deficiency) and new (autosomal-dominant UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiency) genetic defects abolishing induction or amplification of type I IFNs.…”

SARS-CoV-2 desensitizes host cells to interferon through inhibition of the JAK-STAT pathway

“…Being amongst the earliest and most potent of the immune responses, IFN signaling poses an immediate threat to viruses and can quickly eliminate them from the infected cells. Two recent reports have shown that inborn errors in IFN signaling and the presence of anti-IFN auto-antibodies can predispose individuals to a life-threatening COVID-19 disease, highlighting the importance of IFN immunity in SARS-CoV-2 infection 22,23 . Our findings complement these reports and show that SARS-CoV-2 has evolved a suite of mechanisms to counteract the effector functions of interferon.…”

Recovery from COVID-19 in a Child with Chronic Granulomatous Disease and T Cell Lymphopenia

“…This cohort included 4 patients with chronic granulomatous disease (CGD), 3 of whom did well, while one patient with concomitant Burkholderia infection died. Interrogation of the immune response in patients with severe COVID-19 has also revealed the importance of the type I interferon (IFN) pathway in controlling infection, including loss-of-function variants in genes in this pathway and neutralizing antibodies to type I IFNs [7,8]. Here, we present the case of COVID-19 in a patient with CGD and T cell deficiency due to failed hematopoietic cell transplantation (HCT) who recovered with supportive care.…”