Targeting the TCA Cycle to Reduce Post-TB Mortality

Researchers at Baylor College of Medicine and other institutions have discovered a mechanism that causes the long-term decline in immune response observed after tuberculosis (TB) is successfully treated. Their findings, published in the Proceedings of the National Academy of Sciences, point to a potential new approach to restoring immune responsiveness and lowering mortality risk following severe infections.

Sepsis and TB are associated with loss of protective immune responses and increased mortality post successful treatment. In the current study, we investigated what mediated the perturbation of immune function after severe infections.”

Dr. Andrew DiNardo, Study Corresponding Author and Associate Professor, Baylor College of Medicine

Scholars were aware that severe and protracted infections in both people and animals cause enduring, persistent epigenetic alterations. These modifications are to the chemical labels on DNA that instruct body cells which genes to activate or deactivate.

For example, tuberculosis reduces immune responsiveness by adding extra methyl chemical tags (DNA methylation) to genes involved in immune responses. As a result, the production of proteins that mediate immune defense decreases while infection susceptibility increases. However, the mechanisms that cause epigenetic changes during infections were unclear.

Previous research has identified the tricarboxylic acid (TCA) cycle, a critical component of cellular metabolism, as a metabolic driver of the epigenetic landscape in cancer. DiNardo and colleagues wanted to know if TCA regulated epigenetics, specifically DNA methylation, following infection-induced immune tolerance.

The researchers discovered that human immune cells treated in the lab with bacterial lipopolysaccharide, a bacterial product, and Mycobacterium tuberculosis, the bacteria that causes tuberculosis, developed immune tolerance.

They also discovered that patients with sepsis and tuberculosis have increased TCA activation, which is associated with DNA methylation.

When TB patients received standard care, including therapy and antibiotics, as well as everolimus, an inhibitor of TCA activation, the damaging methylation changes to their DNA were reduced, implying that it can aid in immune system restoration after severe infections.

“Tuberculosis is an interesting disease. By the time a person is diagnosed, they have had symptoms for over three months. By adding everolimus to standard TB antibiotic treatment, the number of detrimental DNA methylation marks is reduced six months into the disease process. It is promising that we can induce epigenetic healing,” DiNardo added.

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

The researchers’ next step is to determine which post-TB epigenetic marks are linked to increased morbidity and mortality. Following that, they hope to determine which individuals would benefit the most from a host-directed therapy capable of healing epigenetic scars.