Why do some people develop life-threatening COVID-19?

Why do some otherwise healthy people develop life-threatening COVID-19 symptoms? According to results published out of the COVID Human Genetic Effort — an ongoing international project spanning over 50 sequencing hubs and hundreds of hospitals around the world — more than 10% of healthy people who develop severe COVID-19 produce misguided antibodies that attack the patient’s own immune system, rather than the invading virus. At least another 3.5% carry genetic mutations that impair their immune response to the virus.

The international research found that in some patients who lacked type I interferon, mutations in a set of 13 proteins crucial for protecting cells and the body from viruses were associated with severe COVID-19 infections.

Published in two papers in Science, the findings help explain why some people develop much more severe COVID-19 disease than others in their age group. These patients include those who required admission to the intensive care unit despite being in their 20s and otherwise healthy. The findings may also provide a molecular explanation for why more men than women die from the disease.

“These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19. And, at least in theory, such interferon problems could be treated with existing medications and interventions,” said Professor Jean-Laurent Casanova, Head of the St Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University and a Howard Hughes Medical Institute investigator.

Murdoch Children’s Research Institute (MCRI) Professor John Christodoulou, co-leading the Australian arm of the COVID Human Genetic Effort, said the two papers provide a potential explanation for the severe COVID-19 infection seen in up to 15% of cases.

“The way SARS-CoV-2 affects people differently has been puzzling. The virus can cause a symptom-free infection and go away quietly, or it can kill in a few days,” he said.

“The researchers sequenced genes for 13 proteins that are very important for protecting against viral infections, and in 3.5% of individuals with severe COVID-19 pneumonia changes in a number of these genes were identified. The changes compromised their ability to protect against COVID-19 infection by impairing patients’ ability to make type I interferon.

“Also, 10% of individuals with severe COVID-19 infection had auto-antibodies to type I interferon, neutralising the early protective effect of innate immunity. Importantly, 95% of these individuals were men, which might explain at least some of the sex differences we see in COVID-19 infection, which tends to affect males more severely.”

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