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Genetic and Immunologic Underpinnings of Severe COVID-19

November 23, 2020

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Pandemic
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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, a study has enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

The study, published in the journal Science (24 September 2020), found that more than 10% of people who develop severe COVID-19 have autoantibodies that attack the immune system rather than the virus that causes the disease. 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.

These findings are the first published results from the COVID Human Genetic Effort, an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals. Results show 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.

Articles:

1.     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).

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

Source: NIH

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