Genetic screen reveals protein primed to stop COVID-19 virus

Vaccines that spur the creation of antibodies designed to attack specific spike proteins of the SARS-CoV-2 virus have been the principal defense against COVID-19. However, Yale researchers have found that local cells that line airways of the respiratory system and other tissues possess a protein that can immediately block the invading virus before it has a chance to spread.

The findings were published July 12 in the journal Nature.

“The protein acts at the very beginning of viral replication and could offer new ways to treat viral infections,” said senior author John MacMicking, a tenured associate professor of microbial pathogenesis and of immunobiology at Yale, a member of the Yale Systems Biology Institute on Yale’s West Campus, and an investigator at the Howard Hughes Medical Institute.

The Yale team, led by MacMicking lab members Dijin Xu, an associate scientist at Yale School of Medicine, and Weiqian Jiang, an immunobiology graduate student at Yale, and both first authors on the paper, scanned the human genome for genes that might interfere with ability of SARS-CoV-2 virus to replicate inside cells. Among several possibilities, they found that one gene in particular, phospholipid scramblase 1 (PLSCR1), interfered with the ability of the COVID-19 virus to infect human lung cells. Parallel studies have shown that individuals with a mutation that inhibited the protein’s activity were more likely to suffer severe cases of COVID-19.

The Yale team found that PLSCR1 blocked the ability of the original SARS-CoV-2 virus, as well as the Delta and Omicron variants, from infecting healthy cells.

Unlike antibodies, which are products of B-cells and the adaptive immune system and memorize specific pathogens, PLSCR1 is part of the innate immune system and can also respond to instructions from T-cells, which recognize viral invaders.

If scientists can develop a way to activate PLSCR1, the new findings indicate, it could provide an additional therapeutic option for COVID-19 and, potentially, other viruses. In addition, the researchers say, genetic tests could help identify individuals harboring PLSCR1 mutations,  putting them at higher risk of severe cases of infection.