Project Summary There is immense interindividual clinical variability in humans infected with SARS-CoV-2, ranging from silent infection to lethal COVID-19. The first breakthrough to crack this enigma came from the field of inborn errors of immunity (IEI). In an international cohort of 659 patients, we reported 23 patients with IEIs at eight influenza susceptibility loci that govern TLR3- and IRF7-dependent type I interferon (IFN) immunity (3.5%), including four unrelated patients with autosomal recessive IRF7 or IFNAR1 deficiency. We also reported an additional 101 patients with neutralizing autoantibodies (auto-Abs) against type I IFN (10.2% of 987), who were auto-immune phenocopies of the patients with IEI. Interestingly, 94% of the patients with auto-Ab against type I IFN were men, and one of the six sick women had X-linked dominant incontinentia pigmenti (IP), suggesting X-linked inheritance in at least some of the patients. Collectively, these patients account for about 13.5% of life-threatening COVID- 19 cases studied. We now hypothesize that other IEI that result in abnormal (i) production or amplification of type I IFN, (ii) activity of soluble type I IFNs (via neutralizing auto-Abs), or (iii) response to type I IFN (in terms of interferon stimulated gene (ISG) activity), can underlie life-threatening COVID-19 in other patients. To tackle these three specific aims, we benefit from an international recruitment from the COVID Human Genetic Effort (https://www.covidhge.com). Our preliminary data are very strong. First, we have found 215 patients with predicted loss-of-function (pLOF) variants at 157 loci associated with production or amplification of type I IFN, including one patient homozygous for a pLOF variants in NLRC3, two patients heterozygous for pLOF variants in DDX58/RIG-I, and six patients heterozygous for pLOF variants in subtypes of type I or III IFNs. Second, among patients with auto-Ab against type I IFN, we identified a patient hemizygous for a pLOF in X-linked SASH3. In addition, we found that 25% of patients with IP, which is associated with severely skewed X-inactivation, have auto-Ab against type I IFN, further suggesting an X-linked basis of auto-Ab to type I IFN production. Third, we found 24 patients with pLOF variants in 18 ISGs. We have shown that the international path-breaking program we established in only 6 months is highly efficient, as it resulted in a paradigm-shifting discovery. Our new program will benefit from this momentum. Our future discoveries of new inborn errors of type I IFN immunity underlying life-threatening COVID-19 pneumonia will pave the way for new diagnostic and therapeutic strategies to better manage patients infected with SARS-CoV-2 at risk of severe disease. Selected patients may benefit from subcutaneous or nebulized IFN-a or IFN-b (defect in type I IFN production or amplification), plasmapheresis and/or B cell depletion (neutralizing auto-Abs against type I IFNs), or other therapies, including mAbs against SARS-CoV-2 (defects of ISGs).

Project Narrative We reported that at least 13.5% of patients with life-threatening COVID-19 have inborn errors of TLR3- and IRF7-dependent type I IFN immunity, or neutralizing auto-Ab against type I IFNs. We now hypothesize that other genetic defects of production, activity, or impact of type I IFNs can underlie life-threatening COVID-19 in other patients. Our preliminary data suggest that these different forms of IEI impairing anti-viral type I IFN immunity can underlie life-threatening COVID-19 in a sizeable proportion of cases.