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Sci Immunol. 2017 Mar;2(9). pii: eaaj1789. doi: 10.1126/sciimmunol.aaj1789. Epub 2017 Mar 24.

Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis.

Author information

1
Singapore Immunology Network, Agency for Science, Technology and Research (A STAR), Singapore 138648, Singapore.
2
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
3
Tulane National Primate Research Center, Covington, LA 70433, USA.
4
Public Health Research Institute of Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103, USA.
5
New York City College of Technology, Brooklyn, NY 11201, USA.
6
Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA.
7
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.

Abstract

Mycobacterium tuberculosis (Mtb) executes a plethora of immune-evasive mechanisms, which contribute to its pathogenesis, limited efficacy of current therapy, and the emergence of drug-resistant strains. This has led to resurgence in attempts to develop new therapeutic strategies/targets against tuberculosis (TB). We show that Mtb down-regulates sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, in monocytes/macrophages, TB animal models, and TB patients with active disease. Activation of SIRT1 reduced intracellular growth of drug-susceptible and drug-resistant strains of Mtb and induced phagosome-lysosome fusion and autophagy in a SIRT1-dependent manner. SIRT1 activation dampened Mtb-mediated persistent inflammatory responses via deacetylation of RelA/p65, leading to impaired binding of RelA/p65 on the promoter of inflammatory genes. In Mtb-infected mice, the use of SIRT1 activators ameliorated lung pathology, reduced chronic inflammation, and enhanced efficacy of anti-TB drug. Mass cytometry-based high-dimensional analysis revealed that SIRT1 activation mediated modulation of lung myeloid cells in Mtb-infected mice. Myeloid cell-specific SIRT1 knockout mice display increased inflammatory responses and susceptibility to Mtb infection. Collectively, these results provide a link between SIRT1 activation and TB pathogenesis and indicate a potential of SIRT1 activators in designing an effective and clinically relevant host-directed therapies for TB.

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