New research from the University of Kansas shows a “risk gene” linked to higher odds of developing autoimmune diseases such as diabetes or lupus may also provide a survival advantage fighting viral infections like coronavirus. The research centers on a gene called PTPN22, which carries a mutation, 1858C>T (R620W), found in roughly one in 10 people in North America.
The results, which could lead to better antiviral therapies, appeared recently in the journal Proceedings of the National Academy of Sciences.
“We really focus on how mutations that are very common in the human population might impact antiviral immune responses and our immune response to cancers,” said senior author Robin Orozco, assistant professor of molecular biosciences at KU, who oversaw the research. “We’re trying to understand a more basic question — what are these mutations doing right that, when you don’t have them, is going wrong and leading to disease?”
Orozco’s research team previously showed beneficial aspects of this mutation, finding that mice carrying it are protected from chronic viral infection as well as tumors.
“Autoimmunity, tumors and chronic viral infections all share something in common — they’re chronic diseases,” she said. “When we think about how the immune system mediates chronic disease, there are similarities in this long-term battle between the immune system and the disease.”
Ramp up quickly
In contrast, Orozco said, during an acute infection the immune system must ramp up quickly and then shut down quickly to avoid causing more harm than good.
“So, we were curious — if this mutation provides benefits in chronic conditions, what happens in an acute, potentially lethal infection?” she said.
To study this, Orozco collaborated with coronavirus biologist Anthony Fehr, KU associate professor of molecular biosciences, and used a mouse model of coronavirus infection. In this model, acute infection affects the liver and is lethal in about 50% of mice.
“What we found was that mice with this mutation were almost 100% protected from the lethal infection,” she said. “That was surprising and exciting. It led us to ask why.”
Natural killer cells
The KU team found the mutation enhances the function of natural killer cells in fighting coronavirus, a role that is not significant in mice without the mutation.
“It makes them relevant in this infection — they become so effective that they provide a protective benefit,” Orozco said. “In normal mice, removing natural killer cells had no effect. But in mice with the mutation, these enhanced cells became key players.”
That finding led Orozco’s team to consider new therapeutic approaches.
“Instead of only focusing on cells that are already important, we might ask whether there are cells that appear unimportant but could become powerful if their function were enhanced,” she said. “In this case, boosting natural killer cell activity — specifically increasing interferon gamma, perforin and granzyme — made them effective against infection.”
Immune mechanisms
The KU researcher said even when natural killer cells were removed from mutated mice, the animals still survived at high rates, despite higher viral loads.
“This suggests that other immune mechanisms also contribute to survival,” she said. “It also shows that viral load is not always directly linked to survival outcomes.”
Although about 10% of the North American population carries this mutation, the findings could apply to people without it.
“It suggests that enhancing similar immune pathways might provide benefits more broadly, even if someone doesn’t naturally carry the variant,” Orozco said. “The findings suggest that multiple components of the immune system work together to fight infection. They also highlight the potential for enhancing immune responses in ways that are not obvious from studying normal conditions alone.”
Further implications
The mutation’s effects may also have implications for autoimmunity, cancer and chronic infections, as well as emerging therapies that use natural killer cells.
“We’re now working to test whether the same mutation provides protection in lung infections, which are more relevant to respiratory viruses like SARS-CoV-2,” Orozco said. “Because immune responses differ by tissue, results in the liver may not directly translate to the lungs. Future work will examine how this mutation functions across different organs.”
Orozco and Fehr’s collaborators were led by first author Alec Bevis, a graduate student in the KU Department of Molecular Biosciences, working alongside co-author Kathryn J. L. H. Rosa, then an undergraduate researcher now pursuing a doctorate. Additional KU co-authors included research staff members Nancy Schwarting and Tammy Cockerham as well as Catherine Kerr, a graduate researcher. Sunil More of Oklahoma State University performed liver histology to assess tissue damage in collaboration with the KU team.
This work was supported by the NIH Chemical Biology of Infectious Disease COBRE, University of Kansas startup funds, an NIH Chemical Biology Training Grant and the MARC and McNair programs.
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