Researchers at Baylor College of Medicine and other institutions have discovered a mechanism that leads to a decline in immune response following successful treatment of tuberculosis (TB). This decline in immune response can increase mortality risk after severe infections, such as sepsis. The researchers found that severe and chronic infections can result in persistent epigenetic changes, which are alterations in chemical markings on DNA that affect gene expression. In the case of TB, these changes dampen immune responsiveness by adding extra methyl chemical tags to certain genes involved in immune responses.
The researchers focused on the tricarboxylic acid (TCA) cycle, a key part of cellular metabolism, to see if it also regulated epigenetic changes, specifically DNA methylation, after infection-induced immune tolerance. They found that human immune cells treated with bacterial products became immune tolerant and that patients with both sepsis and TB had increased TCA activation, correlating with DNA methylation. When TB patients were treated with everolimus, an inhibitor of TCA activation, in addition to standard care and antibiotics, the damaging methylation changes to their DNA were reduced, suggesting a potential way to restore immune function after severe infections.
The findings suggest that everolimus treatment could help reduce detrimental DNA methylation marks in TB patients after six months of treatment, potentially inducing epigenetic healing. Dr. Cristian Coarfa, a co-author of the study, believes that these approaches are not limited to tuberculosis and may play a role in other infectious diseases as well. The researchers plan to identify which post-TB epigenetic marks lead to increased morbidity and mortality, and to determine which individuals would benefit the most from host-directed therapy to heal epigenetic scars.
Dr. Andrew DiNardo, the corresponding author of the study, explained that sepsis and TB are associated with loss of protective immune responses and increased mortality post successful treatment. By investigating the mechanisms that mediate the perturbation of immune function after severe infections, the researchers were able to uncover the role of the TCA cycle in driving epigenetic changes in response to infections. Their discoveries could lead to a paradigm shift in the treatment of infectious diseases, offering new ways to restore immune responsiveness and reduce mortality risk post-infection.
The study provides valuable insights into the importance of understanding epigenetic changes in response to severe infections and the potential for targeted therapies like everolimus to mitigate the detrimental effects on the immune system. By identifying specific epigenetic marks that contribute to increased morbidity and mortality post-TB, the researchers hope to develop personalized approaches to host-directed therapy that can effectively heal these epigenetic scars and improve patient outcomes. These findings have the potential to revolutionize the treatment of infectious diseases and offer new strategies to combat the long-term effects of severe infections on the immune system.