Researchers have identified a new genetic risk factor for SARS-CoV-2 infection.
The work provides new insights into the virus’ ability to invade human cells. SARS-CoV-2 is the virus that spreads COVID-19.
The study, led by immunologist Declan McCole at the University of California, Riverside, shows that a loss-of-function variant in the phosphatase gene PTPN2, commonly associated with autoimmune diseases, can increase expression of the SARS-CoV-2 receptor ACE2, making cells more susceptible to viral invasion.
A loss-of-function variant is a genetic modification that disrupts the normal function of a protein, inactivating or severely impairing it. ACE2, a protein on the surface of many cell types, acts as the receptor for the SARS-CoV-2 virus and allows it to infect cells.
“Our findings suggest that individuals with reduced PTPN2 activity may face a higher risk of infection due to the upregulation of ACE2, which serves as the entry point for SARS-CoV-2 into human cells,” says McCole, a professor of biomedical sciences in the UC Riverside School of Medicine.
“PTPN2, which is expressed in cells throughout the body, normally removes a phosphate from other proteins and enzymes, thus reducing their activity. It acts as a brake. If you have a loss of function in PTPN2, then the brake isn’t working well, and you get more inflammatory signaling.”
The discovery offers a deeper understanding of how genetic factors influence susceptibility to COVID-19 and suggests potential therapeutic avenues for mitigating this risk. The study used human intestinal tissues, human cells, and mouse models.
McCole explains that by pinpointing PTPN2 as a new genetic factor, the research team uncovered a critical pathway that can influence how the body responds to SARS-CoV-2 infection.
“We show that a variant of this gene, which has long been linked to autoimmune disorders, can make certain cells more vulnerable to the virus,” he says.
“Our study also shows that this risk can be mitigated with Tofacitinib, a widely used JAK inhibitor, offering potential new treatment options for patients at higher genetic risk. Tofacitinib, approved to treat ulcerative colitis, reversed the increased ACE2 expression on lung, intestinal, and immune cells, thus reducing susceptibility to viral invasion.”
Janus kinase (JAK) inhibitors are a class of drugs that are being widely used to treat chronic inflammatory diseases and immune-mediated diseases.
“Tofacitinib’s ability to reduce ACE2 expression and lower the susceptibility of immune cells to the virus could be key in addressing the pandemic more effectively, especially in vulnerable populations,” McCole says.
“Our findings lays the groundwork for further clinical trials to explore the therapeutic potential of JAK inhibitors in preventing or treating SARS-CoV-2 infection, as well as offering new insights into the complex interactions between the immune system, genetics, and viral susceptibility.”
The research appears in Cellular and Molecular Gastroenterology and Hepatology.
Additional researchers from UC Riverside, Colorado State University in Fort Collins, McGill University in Canada, UC San Diego, the University of Zurich in Switzerland, and the Beckman Research Institute of City of Hope in California contributed to the work.
Critical parts of the research were performed in the UCR Biosafety level 3 (BSL-3) lab used to study infectious agents or toxins that may be transmitted through the air.
Support for the research came via grants from the National Institutes of Health, a City of Hope-UC Riverside Biomedical Research Initiative award, and a postdoctoral research stipend from the Swiss National Science Foundation.
Source: UC Riverside
