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

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Science Immunology  24 Mar 2017:
Vol. 2, Issue 9, eaaj1789
DOI: 10.1126/sciimmunol.aaj1789

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Mtb faces sirtuin death

Mycobacterium tuberculosis (Mtb) is the poster child for drug resistance, and new therapies are needed to combat this reemerging infection. Now, Cheng et al. report that Mtb infection down-regulates sirtuin 1, a NAD+-dependent deacetylase, in myeloid cells in animal models and patients with active disease. Activating sirtuin 1 inhibited intracellular growth of Mtb and persistent inflammatory responses, decreasing lung pathology. Sirtuin 1 activation also enhanced the efficacy of a first-line antituberculosis drug. These effects may be due, in part, to myeloid cell modulation, because mice with myeloid cell–specific SIRT1 deficiency had both increased inflammation and higher susceptibility to infection than wild-type controls. Thus, sirtuin 1 may be a target for host-directed therapy for Mtb.


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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