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

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    Authors
    Cheng, Catherine Y.
    Martinez, Nuria M.
    West, Kim
    Kornfeld, Hardy
    Singhal, Amit
    UMass Chan Affiliations
    Department of Medicine, Division of Pulmonary, Allergy And Critical Care Medicine
    Document Type
    Journal Article
    Publication Date
    2017-03-01
    Keywords
    Immunology of Infectious Disease
    Immunopathology
    Immunoprophylaxis and Therapy
    Virus Diseases
    
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505666/
    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.
    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
    DOI
    10.1126/sciimmunol.aaj1789
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/40330
    PubMed ID
    28707004
    Notes

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

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    10.1126/sciimmunol.aaj1789
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