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- W4313405723 abstract "Abstract Mycobacterium tuberculosis (Mtb) infects and grows in human macrophages unless they are activated earlier using IFN-γ. IFN-γ polarized M1-Macrophages (MΦs) and IL-4 driven M2-MΦs respectively kill Mtb or are permissive. Mtb infected M1-MΦs showed an increased expression of iNOS and autophagy-regulating ATGs compared to M2-MΦs. Despite increased bactericidal function, M1-MΦs were unable to eradicate Mtb. Hypothesis Because M1- and M2-MΦs differentially expressed Sirtuin1, 2, 3 and Sirt5, we hypothesized that, Sirtuin-dependent histone deacetylation would affect gene expression and bactericidal function Methods M0 (naive), M1 or M2-MΦs were treated with inhibitors of Sirtuin1, Sirt2, Sirt3 and Sirt5 followed by Mtb infection, and evaluation of histone modifications using a novel triomics approach. Viability of Mtb was measured before and after Sirtuin blockade and correlated to mRNA expression for iNOS and ATG5 using qPCR. Results a) Relative to uninfected M0-MΦs, M1-MΦs showed higher levels of histone acetylation followed by M2-MΦs. b) Mtb infection reduced global histone acetylation in all three MΦ phenotypes, with an concurrent increase in histone methylation. c) Blockade of Sirt1, 2, 3 but not Sirt5 led to a dramatic restoration of histone acetylation in all three phenotypes, although M2-MΦs were still resistant to Sirt3 inhibitors. d) M0, M1- and M2-MΦs killed Mtb more effectively after Sirt2 blockade compared to Sirt1, 3 and 5 inhibition, which was associated with an increase in mRNA for iNOS and ATG5. Conclusion We conclude that Mtb decreases histone acetylome of human MΦs and Sirtuin inhibitors provide a new epigenetic mechanism to restore macrophage bactericidal function against tuberculosis. Supported by NIH NIAID RO1 AI-122070 and AI-161015." @default.
- W4313405723 created "2023-01-06" @default.
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- W4313405723 date "2022-05-01" @default.
- W4313405723 modified "2023-10-16" @default.
- W4313405723 title "Mycobacterium tuberculosis reduces global histone acetylation in human macrophages which is restored by Sirtuin inhibitors" @default.
- W4313405723 doi "https://doi.org/10.4049/jimmunol.208.supp.110.05" @default.
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