Bibliographic Details
| Title: |
TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance. |
| Authors: |
Abhimanyu, Longlax, Santiago Carrero, Tomoki Nishiguchi, Ladki, Malik, Sheikh, Daanish, Martinez, Amera L., Mace, Emily M., Grimm, Sandra L., Caldwell, Thaleia, Varela, Alexandra Portillo, Sekhar, Rajagopal V., Mandalakas, Anna M., Mlotshwa, Mandla, Ginidza, Sibuse, Cirillo, Jeffrey D., Wallis, Robert S., Netea, Mihai G., van Crevel, Reinout, Coarfa, Cristian, DiNardo, Andrew R. |
| Source: |
Proceedings of the National Academy of Sciences of the United States of America; 10/8/2024, Vol. 121 Issue 41, p1-S6, 17p |
| Subject Terms: |
DNA methylation, MYCOBACTERIUM tuberculosis, IMMUNOLOGICAL tolerance, ISOCITRATE dehydrogenase, TRICARBOXYLIC acids |
| 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
