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- Title
Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis.
- Authors
Cheng, Catherine Y.; Gutierrez, Nuria M.; Marzuki, Mardiana B.; Xiaohua Lu; Foreman, Taylor W.; Paleja, Bhairav; Lee, Bernett; Balachander, Akhila; Jinmiao Chen; Tsenova, Liana; Kurepina, Natalia; Teng, Karen W. W.; West, Kim; Mehra, Smriti; Zolezzi, Francesca; Poidinger, Michael; Kreiswirth, Barry; Kaushal, Deepak; Kornfeld, Hardy; Newell, Evan W.
- 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.
- Subjects
MYCOBACTERIUM tuberculosis; MULTIDRUG-resistant tuberculosis; MYCOBACTERIAL disease treatment; ANTIBIOTICS; CYTOMETRY
- Publication
Science Immunology, 2017, Vol 2, Issue 9, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.aaj1789