Genetic mutation linked to higher SARS-CoV-2 risk

(Press-News.org) RIVERSIDE, Calif. -- Researchers have identified a novel genetic risk factor for SARS-CoV-2 infection, providing 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,” said McCole, a professor of biomedical sciences in the UCR 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, published in Cellular and Molecular Gastroenterology and Hepatology, used human intestinal tissues, human cells, and mouse models.

McCole explained that by pinpointing PTPN2 as a novel 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 said. “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 said. “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.”

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. The research was supported by 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.

McCole was joined in the study by Marianne R. Spalinger, Golshid Sanati, Pritha Chatterjee, Rong Hai, Jiang Li, and Alina N. Santos of UCR; Tara M. Nordgren of Colorado State University in Fort Collins; Michel L. Tremblay of McGill University in Canada; Lars Eckmann, Elaine Hanson, and Brigid S. Boland of UC San Diego; Michael Scharl of the University of Zurich in Switzerland; and Xiwei Wu of the Beckman Research Institute of City of Hope in California.

The research paper is titled “Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.”

The University of California, Riverside is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California's diverse culture, UCR's enrollment is more than 26,000 students. The campus opened a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual impact of more than $2.7 billion on the U.S. economy. To learn more, visit www.ucr.edu.

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