Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis
Department of Medicine, Division of Pulmonary, Allergy And Critical Care Medicine
Immunology of Infectious Disease | Immunopathology | Immunoprophylaxis and Therapy | Virus Diseases
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.
DOI of Published Version
Sci Immunol. 2017 Mar;2(9). pii: eaaj1789. doi: 10.1126/sciimmunol.aaj1789. Epub 2017 Mar 24. Link to article on publisher's site
Cheng, Catherine Y.; Martinez, Nuria M.; West, Kim; Kornfeld, Hardy; and Singhal, Amit, "Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis" (2017). Open Access Articles. 3130.