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).