表观遗传学
DNA甲基化
生物
柠檬酸循环
免疫系统
结核分枝杆菌
异柠檬酸脱氢酶
癌症研究
肺结核
免疫学
微生物学
新陈代谢
医学
生物化学
酶
基因表达
病理
基因
作者
Abhimanyu Abhimanyu,Santiago Carrero Longlax,Tomoki Nishiguchi,Malik Ladki,Daanish Sheikh,Amera L. Martinez,Emily M. Mace,Sandra L. Grimm,Thaleia Caldwell,Aimilia Varela,Rajagopal V. Sekhar,Anna M. Mandalakas,Mandla Mlotshwa,Sibuse Ginidza,Jeffrey D. Cirillo,Robert S. Wallis,Simone J.C.F.M. Moorlag,Reinout van Crevel,Cristian Coarfa,Andrew R. DiNardo
标识
DOI:10.1073/pnas.2404841121
摘要
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.
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