TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all cause post-infectious morbidity and mortality. We show that TCA cycle also regulates epigenetics, specifically DNA methylation, after infection induced immune tolerance. This data from TB patients who received everolimus with standard of care antibiotics, and have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars. Bisulphite converted DNA was evaluated from a TB cohort from South Africa. TB patients were treated with standard of care (SOC) anti-TB Therapy with or without Everolimus . DNA methylation was evaluated from cryopreserved PBMCs at the end of TB treatment (day 180).