November 2, 2020Immunology
New findings by scientists at the National Institutes of Health and their collaborators help explain why some people with COVID-19 develop severe disease. The findings also may provide the first molecular explanation for why more men than women die from COVID-19.
Th following results are the first published results from the COVID Human Genetic Effort, it was found that more than 10% of people who develop severe COVID-19 have misguided antibodies -- autoantibodies -- that attack the immune system rather than the virus that causes the disease. In addition, another 3.5% or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that impacts immunity. Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies or -- because of a faulty gene -- were produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.
For the study, the authors discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known-to-be-critical in the body's defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2. Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the authors also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of interferon type I.
Q Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4570 (2020).
P Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4585 (2020).