Perhaps the most unnerving aspect of COVID-19 is its startling range of severity: from completely asymptomatic to deadly. Starting early in the pandemic, researchers identified factors that put people at risk of a serious case of the disease, such as advanced age, having certain chronic diseases and being male. But these demographic trends do not get at the biological mechanisms that actually cause a life-threatening infection. Nor do they explain why some young, fit, healthy people become mortally ill from the SARS-CoV-2 virus.
Two related papers published in Science onSeptember 24 begin to address these mysteries. They may also partially account for men’s greater vulnerability to the virus and point the way to possible treatments and protective measures. Both studies highlight the critical role of a class of immune system proteins called interferons, so named because they interfere with the replication of viruses.
The new papers were produced by the COVID Human Genetic Effort, a huge international consortium of researchers hunting for genetic mutations that either make individuals unusually susceptible to SARS-CoV-2 or confer exceptional resistance. The consortium is co-led by Jean-Laurent Casanova of the Rockefeller University and Helen Su of the National Institute of Allergy and Infectious Diseases, who are co-senior authors of both of the studies.
In their first paper, the researchers compared DNA from 659 gravely ill COVID-19 patients from around the world with DNA from a control group of 534 infected people who were only mildly affected by the novel coronavirus or did not have symptoms. The scientists specifically looked for mutations that would impair the production of type I interferons—a set of proteins made by every cell in the body that comprise a first-line defense against viruses. Previous work by Casanova and others showed that such mutations left people extremely vulnerable to influenza and other viruses. As it turned out, some of the same mutations associated with life-threatening flu were also present in 3.5 percent of patients with life-threatening COVID-19. No one in the new study’s control group had these mutations.
The second paper focuses on another mechanism that disables interferon responses in patients with severe COVID-19. In this set of studies, researchers examined blood samples from 987 such individuals and discovered that 13.7 percent contained antibodies—dubbed “auto-antibodies”—to the patients’ own type I interferons. In 10.2 percent of the subjects, the auto-antibodies completely blocked the action of these critical virus fighters.
Lab experiments showed that when human cells were exposed to plasma (the liquid part of blood) taken from patients with these self-attacking antibodies, the cells could not defend themselves against SARS-CoV-2. The antibodies were found in 12.5 percent of the severely ill men but only 2.6 percent of similarly ill women—making them a possible factor in the higher COVID-19 mortality rate among men. They were also more common in patients older than 65.
Antibodies to the body’s own cytokines, cell-signaling proteins of the immune system that include interferons, have been known to exacerbate other types of infections. The effect is the same as having