Why People With Diabetes Develop Severe COVID-19 – Mechanism Behind Coronavirus Cytokine Storms Revealed

A new study reveals the mechanism behind the cytokine storm during a coronavirus infection.

During the COVID-19 pandemic, clinicians have noted that certain patients are at particularly high risk of developing serious illness or dying from a coronavirus infection. Type 2 diabetes — a condition that affects more than 10 percent of the U.S. population — is one of the leading risk factors for severe COVID-19 disease. New research from UM reveals why this could be and offers hope for a possible therapy.

The culprit seems to be an enzyme called SETDB2. This same enzyme is involved in the non-healing, inflammatory lesions found in people with diabetes. Working in the lab of Katherine Gallagher, MD of the Michigan Medicine Departments of Surgery and Microbiology and Immunology, researcher W. James Melvin, MD, and colleagues decided to investigate a possible link between the enzyme and runaway inflammation. that they saw firsthand in COVID patients in the ICU.

Starting with a mouse model of coronavirus infection, they found that SETDB2 was decreased in immune cells involved in the inflammatory response, called macrophages, from infected mice with diabetes. They later saw the same in monocyte macrophages in the blood of people with diabetes and severe COVID-19.

“We think we have a reason why these patients develop a cytokine storm,” Melvin says.

In the mouse and human models, Melvin and Gallagher noted, when SETDB2 went down, inflammation increased. In addition, they revealed that a pathway known as JAK1/STAT3 regulates SETDB2 in macrophages during coronavirus infection.

Taken together, the results point to a potential therapeutic path. Previous lab findings showed that interferon, a cytokine important for viral immunity, increased SETDB2 in response to wound healing. In their new study, they found that blood serum from ICU patients with diabetes and severe COVID-19 had reduced interferon beta levels compared to patients without diabetes.

“Interferon has been studied as a potential therapy throughout the pandemic, with efforts going back and forth between attempts to increase or decrease interferon levels,” Gallagher said. “My feeling is that the efficacy as a therapy will be both patient and timing specific.”

To test this, the research team administered interferon beta to coronavirus-infected diabetic mice and saw that they were able to increase SETDB2 and decrease inflammatory cytokines.

“We’re trying to figure out what controls SETDB2, which is kind of a master regulator of many of these inflammatory cytokines that you hear are elevated in COVID-19, such as IL-1B, TNFalpha and IL-6,” Gallagher explains.

“If you look upstream at what controls SETDB2, interferon is at the top, with JaK1 and STAT3 in the middle. Interferon increases both, increasing SETDB2 in a sort of cascade.”

This is important, she added, because identifying the pathway offers other potential ways to target the enzyme.

“Our research shows that if we can target patients with diabetes with interferon, especially at an early stage of their infection, that can make a big difference.”
— W. James Melvin, MD

Melvin and Gallagher hope the findings of this study will inform ongoing clinical trials of interferon or other downstream components of the pathway, including epigenetic targets, for COVID-19. Their work also emphasizes the need to understand the timing and cell specificity of therapy and to tailor its application to the underlying conditions of patients, especially those with diabetes.

“Our research shows that if we can target patients with diabetes with interferon, especially early in their infection, that can make a big difference,” Melvin said.

Reference: “Coronavirus Induces Diabetic Macrophage-Mediated Inflammation Via SETDB2” by William J. Melvin, Christopher O. Audu, Frank M. Davis, Sriganesh B. Sharma, Amrita Joshi, Aaron DenDekker, Sonya Wolf, Emily Barrett, Kevin Mangum, Xiaofeng Zhou, Monica Bame, Alex Ruan, Andrea Obi, Steven L. Kunkel, Bethany B. Moore, and Katherine A. Gallagher, September 3, 2021, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2101071118

Other UM researchers involved in this research include Christopher O. Audu, Frank M. Davis, Sriganesh B. Sharma, Amrita Joshi, Aaron DenDekker, Sonya Wolf, Emily Barrett, Kevin Mangum, Xiaofeng Zhou, Monica Bame, Alex Ruan, Andrea Obi, Steven L. Kunkel and Bethany B. Moore.