TCA metabolism regulates DNA hypermethylation in LPS and<i>Mycobacterium tuberculosis</i>–induced immune tolerance
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 <i>Mycobacterium tuberculosis</i> 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.
Authors
- Mandla Mlotshwa (ORCID: https://orcid.org/0000-0002-5534-1051)
- Emily Margaret Mace (ORCID: https://orcid.org/0000-0003-0226-7393)
- Robert S. Wallis (ORCID: https://orcid.org/0000-0001-6152-5183)
- Reinout van Crevel
- Jeffrey D. Cirillo (ORCID: https://orcid.org/0000-0003-3058-2702)
- Rajagopal V. Sekhar (ORCID: https://orcid.org/0000-0001-9803-015X)
- Malik Ladki (ORCID: https://orcid.org/0000-0001-8735-5696)
- Anna M. Mandalakas (ORCID: https://orcid.org/0000-0002-8091-3509)
- Cristian Coarfa (ORCID: https://orcid.org/0000-0002-4183-4939)
- Sandra L. Grimm (ORCID: https://orcid.org/0000-0002-0682-3134)
- Amera L. Martinez (ORCID: https://orcid.org/0000-0002-9392-5728)
- Santiago Carrero Longlax (ORCID: https://orcid.org/0000-0001-8731-0105)
- Andrew R. DiNardo (ORCID: https://orcid.org/0000-0001-5990-6470)
- Daanish Sheikh (ORCID: https://orcid.org/0000-0003-2216-034X)
- Tomoki Nishiguchi (ORCID: https://orcid.org/0000-0001-5549-7876)
- Abhimanyu Abhimanyu (ORCID: https://orcid.org/0000-0001-7888-8722)
- Sibuse Ginidza
- Thaleia Caldwell
- Mihai G. Netea
- Alexandra Portillo Varela
Institutions
- University of Bonn (DE)
- Radboud University Nijmegen (NL)
- Baylor College of Medicine (US)
- Vanderbilt University (US)
- University of Johannesburg (ZA)
- Radboud University Medical Center (NL)
- University of Oxford (GB)
- University of Texas Health Science Center at Dallas (US)
- German Center for Infection Research (DE)
- Aurum Institute (ZA)
- Texas Children's Hospital (US)
- Children's Cancer Center (US)
- Vanderbilt Health (US)
- Case Western Reserve University (US)
- Columbia University (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1073/pnas.2404841121
- Citations
- 21
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 4.91
Funders
- Bill and Melinda Gates Foundation
- Cancer Prevention and Research Institute of Texas
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Cancer Center
- Cordis
- Defense Technical Information Center
- National Institute of Allergy and Infectious Diseases
- Fogarty International Center
- National Institute of Environmental Health Sciences
- National Institute on Minority Health and Health Disparities
- NHLBI Division of Intramural Research
- European and Developing Countries Clinical Trials Partnership