Life-Threatening COVID-19: Defective Interferons Unleash Excessive Inflammation

Abstract

The risk of life-threatening COVID-19 pneumonia increases sharply after 65 years of age, but other epidemiological risk factors, genetic or otherwise, are modest. Various rare monogenic inborn errors of type I interferons (IFNs) underlie critical disease, and neutralizing autoantibodies against type I IFNs account for at least 10% of critical cases.

Figure 1

Inborn Errors of Type I IFN Immunity or Autoantibodies against Type I IFNs Underlie Life-Threatening COVID-19 Pneumonia: A Two-Step Model of Pathogenesis Monogenic inborn errors of type I IFN immunity have been found in about 3% of patients with critical COVID-19 pneumonia, and neutralizing autoantibodies against type I IFNs have been found in another 10% of patients. Products of known viral disease-causing genes of the TLR3- and IRF7-dependent type I IFN-inducing pathway or the IFNAR1/IFNAR2-mediated type I IFN-responsive and amplification pathway are presented either in red (when deleterious mutations have been identified in patients with critical COVID-19 pneumonia) or in blue (when no deleterious mutations have been identified in patients with critical COVID-19). Variants of 3 of the 13 loci were known to underlie critical influenza pneumonia (TLR3, IRF7, IRF9). Variants of the other 10 loci were known to underlie other viral illnesses. Variants of two genes can underlie severe influenza or SARS-CoV-2 pneumonia (thick-lined frames, TLR3 and IRF7). Autoantibodies (in red) neutralize the activity of type I IFNs. In this two-step model of pathogenesis, inadequate type I IFN responses during the first few hours and days of infection result in viral spread to the lungs and beyond. This results, 1 to 2 weeks later, in pulmonary and systemic hyperinflammation, largely due to the recruitment of leukocytes, which produce excessive amounts of cytokines. IFN, interferon.