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

• 成果类型: Article
• 署名作者: Abhimanyu; Longlax, Santiago Carrero; Nishiguchi, Tomoki; Ladki, Malik; Sheikh, Daanish; Martinez, Amera L.; Mace, Emily M.; Grimm, Sandra L.; Caldwell, Thaleia; Varela, Alexandra Portillo; V. Sekhar, Rajagopal; Mandalakas, Anna M.; Mlotshwa, Mandla; Ginidza, Sibuse; Cirillo, Jeffrey D.; Wallis, Robert S.; Netea, Mihai G.; van Crevel, Reinout; Coarfa, Cristian; Dinardo, Andrew R.
• 署名单位: Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Columbia University; NewYork-Presbyterian Hospital; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Texas System; German Center for Infection Research; Leibniz Association; Forschungszentrum Borstel; University of Johannesburg; Vanderbilt University; Texas A&M University System; Texas A&M University College Station; University System of Ohio; Case Western Reserve University; Vanderbilt University; Radboud University Nijmegen; University of Bonn; University of Oxford
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13659
• DOI: 10.1073/pnas.2404841121
• 发表日期: 2024-10-08
• 关键词: epigenetic regulation; human monocytes; cell; exhaustion; expression; pd-1; immunosuppression; inhibition; phenotype; pulmonary

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 ylation, after infection- induced immune tolerance. The following studies demonstrate mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.