Researchers have uncovered a mechanism that contributes to the long-term decrease in immune response observed after successful treatment for tuberculosis (TB). Their research indicates a promising new approach to enhance immune responsiveness and lower mortality risks following severe infections.
A team from Baylor College of Medicine, along with other institutions, has revealed a mechanism behind the sustained decline in immune response seen after effective tuberculosis (TB) treatment. Their study, published in the Proceedings of the National Academy of Sciences, highlights a possible new strategy for restoring immune function and minimizing death risk post severe infections .
According to Dr. Andrew DiNardo, the lead author and associate professor at Baylor College of Medicine’s section of infectious diseases and division of pediatric global and immigrant health, “Sepsis—an intense bodily reaction to infection—and TB are linked to a loss of protective immune responses, resulting in higher mortality rates after treatment.” He added, “In this study, we explored the factors responsible for the impairment of immune function following severe infections.”
Researchers had already established that severe and chronic infections in both humans and animals lead to persistent epigenetic modifications. These modifications are changes in the chemical marks on DNA that guide cells on which genes to activate or deactivate.
For example, TB weakens the immune response by appending additional methyl chemical tags (DNA methylation) to specific genes related to immune functions. As a result, the body produces fewer proteins responsible for immune defense, making it more vulnerable to further infections. Nevertheless, the exact processes that trigger these epigenetic changes during infections were unclear.
The TCA cycle’s role in epigenetic changes
Earlier research highlighted the tricarboxylic acid (TCA) cycle, a crucial element of cellular metabolism, as a key player in shaping the epigenetic landscape in cancer. DiNardo and his team aimed to find out whether the TCA cycle also influenced epigenetics, particularly DNA methylation, after infections trigger immune tolerance.
The researchers found that immune cells from humans exposed in the lab to bacterial lipopolysaccharide (a product from bacteria) and Mycobacterium tuberculosis (the TB-causing bacteria) became immune tolerant.
Additionally, they discovered that patients suffering from both sepsis and TB exhibited increased activation of the TCA cycle, which was linked to DNA methylation. When TB patients received standard therapy and antibiotics along with everolimus, a TCA activation inhibitor, the detrimental methylation changes to their DNA were lessened, indicating its potential in restoring the immune system after severe infections.
“TB presents an interesting case. By the time a person is diagnosed, symptoms have usually persisted for over three months. Observing that the addition of everolimus to standard TB antibiotic treatment reduces the adverse DNA methylation marks six months into the illness is encouraging for the possibility of inducing epigenetic healing,” remarked DiNardo.
“Our findings signal a potential shift in perspective,” suggested Dr. Cristian Coarfa, co-author and associate professor of molecular and cellular biology at Baylor. “Our methods could extend beyond tuberculosis. The data we have and the paths we wish to explore imply that these strategies might be applicable in other infectious diseases.”
Moving forward, the researchers aim to pinpoint which post-TB epigenetic markers contribute to increased morbidity and mortality. From this point, they hope to identify which individuals might gain the most from a host-directed therapy that can address epigenetic scars.
