Title

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

UMMS Affiliation

Department of Medicine, Division of Pulmonary, Allergy And Critical Care Medicine

Publication Date

3-1-2017

Document Type

Article

Disciplines

Immunology of Infectious Disease | Immunopathology | Immunoprophylaxis and Therapy | Virus Diseases

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.

DOI of Published Version

10.1126/sciimmunol.aaj1789

Source

Sci Immunol. 2017 Mar;2(9). pii: eaaj1789. doi: 10.1126/sciimmunol.aaj1789. Epub 2017 Mar 24. Link to article on publisher's site

Journal/Book/Conference Title

Science immunology

Comments

Full list of authors omitted for brevity. For full list see article.

Related Resources

Link to Article in PubMed

PubMed ID

28707004