Monogenic immune defects in type I interferon pathways as a risk factor for severe COVID-19 pneumonia

Monogenic defects COVID-19 pneumonia

In the 23 October 2020 issue of Science, Zhang et al. report on early results of the COVID Human Genetic Effort (, established to evaluate whether life-threatening COVID-19 infection in some individuals may be linked to underlying, monogenic inborn errors of immunity.

Patients aged 1 month to 99 years of age (n=659) with life-threatening COVID-19 pneumonia requiring admission to an intensive care unit for mechanical ventilation, septic shock, or critical organ damage were included, along with 534 SARS-CoV-2-positive controls with asymptomatic or mild ambulatory disease.

For this study, the authors examined whole exome or genome sequencing for 13 loci within type I interferon pathways, previously shown to be associated with life-threatening influenza or other viral illness: TLR3 and genes involved in the TLR3-dependent pathway (TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, NEMO/IKBKG) and IRF7 and IRF9 along with genes involved in the IRF7- and IRF9-dependent type I IFN amplification pathway (IFNAR1, IFNAR2, STAT1, and STAT2).

Variants were filtered by minor allele frequency <0.001 and predicted loss of function. Twenty-four variants spanning 8 genes in 23 patients, aged 17 to 77 years, were subsequently confirmed to be deleterious.

Of these, 4 patients were found to have a previously described autosomal recessive defect (IRF7 or IFNAR1), 11 a known autosomal dominant defect (TLR3, TICAM1, TBK1, or IRF3), and 8 a novel autosomal dominant defect (UNC93B1, IRF7, IFNAR1, or IFNAR2).

No other known primary immune defects were identified in these patients, and none had detectable autoantibodies against type I interferon (described elsewhere as another mechanism of susceptibility to COVID-19).

Additionally, IFN-a levels checked in a subset of patients with available samples (n=10) were exceedingly low, in contrast to extremely elevated IFN-a levels in other cohorts of patients with severe COVID-19.

In this large cohort, at least 3.5% of unrelated patients with life-threatening COVID-19 pneumonia had an underlying primary immune defect affecting type I interferon immunity, thought to predispose them to severe viral illness.

The findings establish a critical role of type I interferon immunity in the control of COVID-19 and hold therapeutic implications for type I interferon administration in select patients.

Read More: Science, 2020 Oct 23;370 (6515)