Genetic and immunologic underpinnings of some cases of severe COVID-19

2020

Challenge

The wide variation in the severity of disease caused by SARS-CoV-2, the virus behind COVID-19, has puzzled scientists and clinicians. SARS-CoV-2 can cause anything from a symptom-free infection to death, with many different outcomes in between. Since February 2020, researchers from around the world involved with the COVID Human Genetic Effort have studied thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

Advance

The researchers — co-led by IRP senior investigator Helen Su, M.D., Ph.D., and Jean-Laurent Casanova, M.D., Ph.D., of The Rockefeller University in New York — found that more than 10 percent of people who develop severe COVID-19 have misguided antibodies, called autoantibodies, that interfere with their immune responses rather than attacking the SARS-CoV-2 virus. Moreover, another 3.5 percent or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that affects the immune system. Consequently, both of these groups lack effective immune responses that depend on type I interferons, a set of 17 proteins crucial for protecting the body from viruses.

Impact

These discoveries suggest that people who have certain genetic defects that impair type I interferons or who have autoantibodies that neutralize certain type I interferons may be predisposed to severe disease and death after SARS-CoV-2 infection. These higher-risk individuals could be prioritized for SARS-CoV-2 vaccination. In addition, people who have these risk factors and acquire SARS-CoV-2 may benefit from treatment with interferon-beta or with therapies that remove the autoantibodies that target type I interferons. Additional studies will be needed to determine whether these interventions could prevent poor outcomes, including death, in those patients.

Publications

Zhang Q et al. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. Sep 24. doi: 10.1126/science.abd4570.

Bastard P et al. (2020). Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science. Sep 24. doi: 10.1126/science.abd4585.