Scientists discover common genetic and immunological causes of severe COVID-19

More than 10 per cent of healthy people who develop severe COVID-19 have misguided antibodies that attack the patient's own immune system, rather than the invading virus, new research shows. Another 3.5 per cent, at least, 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. They may also provide the first 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," 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. "And at least in theory, such interferon problems could be treated with existing medications and interventions."

The findings are the first results being published out of the COVID Human Genetic Effort, an ongoing international project spanning over 50 sequencing hubs and hundreds of hospitals around the world including the Murdoch Children's Research Institute (MCRI) and co-led by Professor Casanova and Dr Helen Su at the National Institute of Allergy and Infectious Diseases. The study participants included various nationalities from Asia, Europe, Latin America, and the Middle East. 

MCRI Professor John Christodoulou, co-leading the Australian arm of the COVID Human Genetic Effort, said these two papers provide a potential explanation for the severe COVID-19 infection seen in up to 15 per cent 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 per cent 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 per cent of individuals with severe COVID-19 infection had auto-antibodies to type I interferon, neutralising the early protective effect of innate immunity. Importantly, 95 per cent 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."