Language
English
Publication Date
10-8-2024
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2404841121
PMID
39348545
PMCID
PMC11474056
PubMedCentral® Posted Date
9-30-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.
Keywords
DNA Methylation, Mycobacterium tuberculosis, Humans, Lipopolysaccharides, Citric Acid Cycle, Immune Tolerance, Animals, Tuberculosis, Mice, Epigenesis, Genetic, Succinates, Everolimus, Succinic Acid, immune tolerance, DNA methylation, tuberculosis, sepsis, Rheostat
Published Open-Access
yes
Recommended Citation
Abhimanyu; Longlax, Santiago Carrero; Nishiguchi, Tomoki; et al., "TCA Metabolism Regulates DNA Hypermethylation in LPS and Mycobacterium tuberculosis–Induced Immune Tolerance" (2024). Faculty and Staff Publications. 4380.
https://digitalcommons.library.tmc.edu/baylor_docs/4380