ANN ARBOR – New research from the University of Michigan recently uncovered why people with Type 2 diabetes are at high risk for developing severe cases of COVID-19.
Researchers identified an enzyme called SETDB2 -- the same enzyme that can make inflammatory wounds difficult to heal in diabetics -- as the likely culprit behind severe COVID infections.
After witnessing runaway inflammation in COVID patients in the ICU, researcher W. James Melvin decided to see if there was a possible link between the enzyme and the cases they observed.
Working in Katherine Gallagher’s lab in the Michigan Medicine Departments of Surgery and Microbiology and Immunology, they began with a mouse model of COVID in mice infected with diabetes, where they observed a decrease in SETDB2 in immune cells affected by the inflammatory response.
The immune cells, called macrophages, reacted similarly in people who had diabetes and severe cases of COVID. In people, the researchers observed the same response in monocyte-macrophages based on blood samples.
“We think we have a reason for why these patients are developing a cytokine storm,” Melvin said in a statement.
In both the human and mouse models, Gallagher and Melvin said inflammation went up as SETDB2 went down. Their research also revealed a pathway that regulates SETDB2 in macrophages, known as JAK1/STAT3, during active COVID infection.
Their results indicate a potential therapeutic pathway that could have benefits in reversing the pattern COVID patients with diabetes tend to demonstrate.
The lab previously found that interferon, a key cytokine for viral immunity, was able to increase SETDB2 when responding to wound healing. As part of the new study, the researchers found that blood serum from ICU patients with diabetes and severe COVID infections were more likely to have reduced levels of interferon-beta compared to non-diabetes patients.
“Interferon has been studied throughout the pandemic as a potential therapy, with efforts going back and forth between trying to increase or decrease interferon levels,” Gallagher said in a statement. “My sense is that its efficacy as a therapy will be both patient and timing specific.”
The study team was able to decrease inflammatory cytokines and increase SETDB2 in diabetic COVID-infected mice by administering interferon beta.
“We’re trying to hone in on what controls SETDB2, which is sort of the master regulator of a lot of these inflammatory cytokines that you hear about as being increased in COVID-19, such as IL-1B, TNFalpha, and IL-6,” explained Gallagher in a statement.
“Looking upstream at what’s controlling SETDB2, interferon is at the top end, with JaK1 and STAT3 in the middle. Interferon increases both, which increases SETDB2 in a sort of cascade.”
The significance of identifying the pathway is that it presents researchers with alternative methods of targeting the enzyme, said Gallagher.
“Our research is showing that maybe if we are able to target patients with diabetes with interferon, especially early in their infection, that may actually make a big difference,” Melvin said in a statement.
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