1. Microbiology and Infectious Disease
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Host Sirtuin 2 as an immunotherapeutic target against tuberculosis

  1. Ashima Bhaskar  Is a corresponding author
  2. Santosh Kumar
  3. Mehak Zahoor Khan
  4. Amit Singh
  5. Ved Prakash Dwivedi
  6. Vinay Kumar Nandicoori
  1. National Institute of Immunology, India
  2. International Centre for Genetic Engineering and Biotechnology, India
  3. Indian Institute of Science, India
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Cite this article as: eLife 2020;9:e55415 doi: 10.7554/eLife.55415
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Abstract

Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here we show that Mtb upregulates one of the key epigenetic modulators, NAD+ dependent histone deacetylase Sirtuin 2 (SIRT2), which upon infection translocate to the nucleus and deacetylates histone H3K18, thus modulating the host transcriptome leading to enhanced macrophage activation. Furthermore, in Mtb specific T cells, SIRT2 deacetylates NFκB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracellular growth of both drug-sensitive and resistant strains of Mtb and enhances the efficacy of front line anti-TB drug Isoniazid in the murine model of infection. SIRT2 inhibitor-treated mice display reduced bacillary load, decreased disease pathology and increased Mtb specific protective immune responses. Overall, this study provides a link between Mtb infection, epigenetics and host immune response, which can be exploited to achieve therapeutic benefits.

Data availability

All data generated or analysed during this study are included in the manuscript. Source data files have been provided for all the Figures.

Article and author information

Author details

  1. Ashima Bhaskar

    Signal Transduction Laboratory-1, National Institute of Immunology, New Delhi, India
    For correspondence
    ashimabhaskar@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7367-874X
  2. Santosh Kumar

    Immunobiology, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Mehak Zahoor Khan

    Signal Transduction Laboratory-1, National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Amit Singh

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Ved Prakash Dwivedi

    Immunobiology, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4321-2567
  6. Vinay Kumar Nandicoori

    Signal Transduction Laboratory, National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5682-4178

Funding

Department of Science and Technology, Ministry of Science and Technology (NII/F-56/827/IFAD)

  • Ashima Bhaskar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were carried out in accordance with the guidelines approved by the Animal Ethics Committee of National Institute of Immunology (NII, Approval ID: IAEC#409/16 & IAEC#462/18), New Delhi, India, International Centre for Genetic Engineering and Biotechnology (ICGEB, Approval ID: ICGEB/AH/2015/01/IMM-45), New Delhi, India and the Department of Biotechnology (DBT) Government of India. Mice were ethically sacrificed according to institutional and DBT regulations.

Reviewing Editor

  1. Christina L Stallings, Washington University School of Medicine, United States

Publication history

  1. Received: January 23, 2020
  2. Accepted: July 20, 2020
  3. Accepted Manuscript published: July 22, 2020 (version 1)
  4. Version of Record published: August 3, 2020 (version 2)

Copyright

© 2020, Bhaskar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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