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

Authors :
Abhimanyu
Longlax SC
Nishiguchi T
Ladki M
Sheikh D
Martinez AL
Mace EM
Grimm SL
Caldwell T
Portillo Varela A
Sekhar RV
Mandalakas AM
Mlotshwa M
Ginidza S
Cirillo JD
Wallis RS
Netea MG
van Crevel R
Coarfa C
DiNardo AR
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 08; Vol. 121 (41), pp. e2404841121. Date of Electronic Publication: 2024 Sep 30.
Publication Year :
2024

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.<br />Competing Interests: Competing interests statement:The authors declare no competing interest.

Details

Language :
English
ISSN :
1091-6490
Volume :
121
Issue :
41
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
39348545
Full Text :
https://doi.org/10.1073/pnas.2404841121