Researchers discover mechanism behind immune disruption after serious infections

Researchers at Baylor College of Medicine and collaborating institutions have discovered a mechanism that leads to the long-term decline in immune response seen after successful treatment of tuberculosis (TB). Their conclusions, published in the Proceedings of the National Academy of Sciencessuggest a potential new way to restore immune responsiveness and reduce mortality risk after serious infections.

“Sepsis and tuberculosis are associated with loss of protective immune responses and increased mortality after successful treatment,” said Dr. Andrew DiNardo, corresponding author and associate professor in the Section of Infectious Diseases and Division of Health. Global Pediatric and Immigrant Studies at Baylor College of Medicine. and Texas Children’s Hospital. “In the current study, we investigated what was involved in the disruption of immune function after severe infections.”

Researchers know that severe and chronic infections in humans and animals lead to persistent and long-lasting epigenetic changes. These changes refer to alterations in the chemical markings on DNA that tell the body’s cells which genes to turn on or off.

For example, tuberculosis attenuates immune reactivity by adding additional methyl chemical markers (DNA methylation) to certain genes involved in immune responses. This in turn leads to decreased production of immune defense mediating proteins and increased susceptibility to infections. However, the mechanisms inducing epigenetic changes in infections were unclear.

Previous studies have identified the tricarboxylic acid (TCA) cycle, a key component of cellular metabolism, as a metabolic driver of the cancer epigenetic landscape. DiNardo and colleagues wanted to see if TCA also regulated epigenetics, particularly DNA methylation, after infection-induced immune tolerance.

The team reported that human immune cells treated in the laboratory with bacterial lipopolysaccharide, a bacterial product, and Mycobacterium tuberculosis, the bacteria that causes tuberculosis, became immunotolerant. They also found that patients diagnosed with both sepsis and tuberculosis had increased TCA activation, which correlates with DNA methylation.

When TB patients received standard treatment and antibiotics, as well as everolimus, an inhibitor of TCA activation, damaging changes in their DNA methylation were reduced, suggesting that it may help restore the immune system after serious infections.

“TB is an interesting disease. By the time a person is diagnosed, they have had symptoms for more than three months. By adding everolimus to the standard antibiotic treatment for TB, the number of harmful tuberculosis methylation marks DNA is reduced six months after the onset of the disease process promising that we can induce epigenetic healing,” DiNardo said.

“What we discovered is going to lead to a paradigm shift,” said Dr. Cristian Coarfa, co-author and associate professor of molecular and cellular biology at Baylor. “Our approaches are not limited to tuberculosis. The evidence we have and are trying to build on suggests that these strategies could play a role in other infectious diseases.”

The next step for researchers is to identify post-TB epigenetic marks that lead to increased morbidity and mortality. From there, they would like to determine which people would benefit most from a host-directed therapy that can heal epigenetic scars.