1. Microbiology and Infectious Disease
Download icon

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
Research Article
  • Cited 0
  • Views 898
  • Annotations
Cite this article as: eLife 2020;9:e55415 doi: 10.7554/eLife.55415

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.

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.

Metrics

  • 898
    Page views
  • 188
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Kuan-Yi Lu et al.
    Research Article

    Phosphatidylinositol 3-phosphate (PI(3)P) levels in Plasmodium falciparum correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the Plasmodium stress response was unknown. Here, we used PI3K inhibitors and antimalarial agents to examine the importance of PI(3)P under thermal conditions recapitulating malarial fever. Live cell microscopy using chemical and genetic reporters revealed that PI(3)P stabilizes the digestive vacuole (DV) under heat stress. We demonstrate that heat-induced DV destabilization in PI(3)P-deficient P. falciparum precedes cell death and is reversible after withdrawal of the stress condition and the PI3K inhibitor. A chemoproteomic approach identified PfHsp70-1 as a PI(3)P-binding protein. An Hsp70 inhibitor and knockdown of PfHsp70-1 phenocopy PI(3)P-deficient parasites under heat shock. Furthermore, PfHsp70-1 downregulation hypersensitizes parasites to heat shock and PI3K inhibitors. Our findings underscore a mechanistic link between PI(3)P and PfHsp70-1 and present a novel PI(3)P function in DV stabilization during heat stress.

    1. Cell Biology
    2. Microbiology and Infectious Disease
    Elisa Gómez-Gil et al.
    Research Article Updated

    Cytokinesis, which enables the physical separation of daughter cells once mitosis has been completed, is executed in fungal and animal cells by a contractile actin- and myosin-based ring (CAR). In the fission yeast Schizosaccharomyces pombe, the formin For3 nucleates actin cables and also co-operates for CAR assembly during cytokinesis. Mitogen-activated protein kinases (MAPKs) regulate essential adaptive responses in eukaryotic organisms to environmental changes. We show that the stress-activated protein kinase pathway (SAPK) and its effector, MAPK Sty1, downregulates CAR assembly in S. pombe when its integrity becomes compromised during cytoskeletal damage and stress by reducing For3 levels. Accurate control of For3 levels by the SAPK pathway may thus represent a novel regulatory mechanism of cytokinesis outcome in response to environmental cues. Conversely, SAPK signaling favors CAR assembly and integrity in its close relative Schizosaccharomyces japonicus, revealing a remarkable evolutionary divergence of this response within the fission yeast clade.