Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Abstract

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology

“…The genomewide association meta-analyses that consisted of 49,562 COVID-19 patients from 46 studies across 19 countries indicated that specific mutations of the tyrosine kinase 2 (TYK2) gene could enhance the risk of becoming critically ill with COVID-19, while individuals who carried a variant in the dipeptidyl peptidase 9 (DPP9) gene were at elevated risk of developing critical disease (191,192). Lossof-function mutations in type I IFN (IFN-I) immunity genes (TLR3 and TLR7) might be connected with severe forms of COVID-19 in European populations (193)(194)(195). NLRP3 inflammasome gene variants were correlated with critical COVID-19 in the Brazilian population (196).…”

Loss of STAT2 may be dangerous in a world filled with viruses

“…As is noted by Bucciol, Moens, et al, STAT2 and related genes are under intense selective pressure, presumably driven by viruses. In recent years, it has also become increasingly appreciated that various impairments of type I IFN function, either from inborn errors or anti-IFN autoantibodies, have played an important role in morbidity and mortality from the SARS-CoV-2 pandemic ( 7 , 8 ). Thus, increasing evidence demonstrates that type I IFNs are a critical defense against the ubiquitous threat that viruses pose.…”

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

“…Human genetic variation associated with disease severity has revealed defective innate immune responses as another key determinant in COVID-19 disease outcomes. Patients with inborn errors in components of RNA-sensing and innate signaling pathways, including toll-like receptor 3 (TLR3), TLR7, interferon-regulatory factor 7 (IRF7), type-I IFN (IFN-I) receptors IFNAR1 and IFNAR2, tyrosine kinase 2 (TYK2) and oligoadenylate synthetase 1 (OAS1) are at high risk of developing critical and severe COVID-19 disease 2–4,15,17–19,12,20–22 . The crucial importance of innate-derived IFNs is further underscored by the discovery that up to 15 – 20% of critically ill patients with COVID-19 had preexisting auto-antibodies to IFN-I, which delayed viral clearance 23–26 .…”