Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis.

Autor:	Bobak CA; Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA., Abhimanyu; The Global Tuberculosis Program, Baylor College of Medicine, Houston, TX 77030, USA.; William Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.; Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Natarajan H; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH 03755, USA., Gandhi T; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX 77030, USA., Grimm SL; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX 77030, USA., Nishiguchi T; The Global Tuberculosis Program, Baylor College of Medicine, Houston, TX 77030, USA.; William Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.; Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Koster K; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health, Bryan, TX 77807, USA., Longlax SC; The Global Tuberculosis Program, Baylor College of Medicine, Houston, TX 77030, USA.; William Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.; Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Dlamini Q; Baylor-Swaziland Children's Foundation, Mbabane, Swaziland., Kahari J; Baylor-Swaziland Children's Foundation, Mbabane, Swaziland., Mtetwa G; Baylor-Swaziland Children's Foundation, Mbabane, Swaziland., Cirillo JD; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health, Bryan, TX 77807, USA., O'Malley J; Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.; The Dartmouth Institute, Dartmouth College, Hanover, NH 03755, USA., Hill JE; Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, Canada., Coarfa C; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX 77030, USA., DiNardo AR; The Global Tuberculosis Program, Baylor College of Medicine, Houston, TX 77030, USA.; William Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.; Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Aging [Aging (Albany NY)] 2022 Mar 07; Vol. 14 (5), pp. 2174-2193. Date of Electronic Publication: 2022 Mar 07.
DOI:	10.18632/aging.203936
Abstrakt:	Background: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death. Methods: Guinea pigs were infected with Mycobacterium tuberculosis ( Mtb ) for 45 days, followed by RRBS DNA methylation analysis. In humans, network analysis of differentially expressed genes across three TB cohorts were visualized at the pathway-level. Serum levels of inflammation were measured by ELISA. Horvath (DNA methylation) and RNA-seq biological clocks were used to investigate shifts in chronological age among humans with TB. Results: Guinea pigs with TB demonstrated DNA hypermethylation and showed system-level similarity to humans with TB ( p -value = 0.002). The transcriptome in TB in multiple cohorts was enriched for DNA methylation and cellular senescence. Senescence associated proteins CXCL9, CXCL10, and TNF were elevated in TB patients compared to healthy controls. Humans with TB demonstrate 12.7 years (95% CI: 7.5, 21.9) and 14.38 years (95% CI: 10.23-18.53) of cellular aging as measured by epigenetic and gene expression based cellular clocks, respectively. Conclusions: In both guinea pigs and humans, TB perturbs epigenetic processes, promoting premature cellular aging and inflammation, a plausible means to explain the long-term detrimental health outcomes after TB.
Databáze:	MEDLINE
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