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Immunity gene mutations and autoantibodies linked to severe COVID-19

28 September 2020
Appeared in BioNews 1065

Two new studies highlight the underlying genetic causes that begin to explain why some COVID-19 patients suffer worse symptoms than others.

Scientists from the COVID Human Genetic Effort, a large consortium dedicated to research on COVID-19 and SARS-CoV-2, the virus that causes the disease, published two papers in Science last week that unpick the differences in ability between individuals to respond to coronavirus infection.

Professor Jean-Laurent Casanova, one of the study leaders and senior authors, said: 'These two papers provide the first explanation for why COVID-19 can be so severe in some people, while most others infected by the same virus are okay.' 

In the first study the scientists sequenced the genomes of 659 severely affected patients and of 534 people with mild infections. They found that many people with severe COVID-19 had mutations in the gene responsible for making type 1 interferon, a protein that is released during infection to alert and activate immune cells. Patients with these mutations produced either no or very low levels of interferon, thus giving the virus more time in the body to replicate before the immune system was alerted.

The second study found that 101 out of 987 patients with severe COVID-19 had autoantibodies against their own interferon, while none was found in people with mild or no COVID-19 symptoms. These antibodies neutralise the interferon the body produces, making it ineffective.

This could also explain why men are more often severely affected by the disease. The scientists think that the genetic cause for the autoantibodies could be mutations on the X chromosome. If one carries a defective copy, women have another one that may not have the mutation that can compensate for the defective gene. Men have a Y chromosome and only one X chromosome, so if the X chromosome mutation occurs, the genetic defect will be expressed.   

The study authors expect that more mutations in genes related to the immune defence will be found in COVID-19 patients in the future. So far, the consortium has only analysed mutations in 13 of over 300 interferon related genes. 

As of now it is unclear why these mutations and neutralising antibodies seem to have a much bigger effect during SARS-CoV-2 infection than other viruses, but it might be that the new coronavirus simply requires higher levels of interferon to be fought off. 'We propose that SARS-CoV-2 is a particularly virulent pathogen that imposes a much greater requirement for type 1 interferon than, say, flu,' Dr Vanessa Sancho-Shimizu, a consortium member and physician from Imperial College, London told the Guardian.

The new findings could now be used to improve diagnosis and treatment. If COVID-19 patients were tested at the hospital for autoantibodies and interferon levels, they could receive plasma exchange or interferon supplements.

Auto-antibodies against type I IFNs in patients with life-threatening COVID-19
Science |  24 September 2020
Genetic or immune defects may impair ability to fight COVID-19
The Guardian |  24 September 2020
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Science |  24 September 2020
Some severe COVID-19 cases linked to genetic mutations or antibodies that attack the body
Howard Hughes Medical Institute |  24 September 2020
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