Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome

  1. Savita Lochab
  2. Yogendra Singh
  3. Sagar Sengupta
  4. Vinay Kumar Nandicoori  Is a corresponding author
  1. National Institute of Immunology, India
  2. University of Delhi, India

Abstract

Mycobacterium tuberculosis (Mtb) produces inflections in the host signaling networks to create a favorable milieu for survival. The virulent Mtb strain, Rv caused double strand breaks (DSBs) whereas the non-virulent Ra strain triggered single stranded DNA generation. The effectors secreted by SecA2 pathway were essential and adequate for the genesis of DSBs. Accumulation of DSBs mediated through Rv activates ATM-Chk2 pathway of DNA damage response (DDR) signaling, resulting in altered cell cycle. Instead of the classical ATM-Chk2 DDR, Mtb gains survival advantage through ATM-Akt signaling cascade. Notably, in vivo infection with Mtb led to sustained DSBs and ATM activation during chronic phase of tuberculosis. Addition of ATM inhibitor enhances isoniazid mediated Mtb clearance in macrophages as well as in murine infection model, suggesting its utility for host directed adjunct therapy. Collectively, data suggests that DSBs inflicted by SecA2 secretome of Mtb provides survival niche through activation of ATM kinase.

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Numerical data for graphs is provided as a Source Data File.

Article and author information

Author details

  1. Savita Lochab

    Signal Transduction Laboratory, National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Yogendra Singh

    Department of Zoology, University of Delhi, Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Sagar Sengupta

    Signal Transduction Laboratory, National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Vinay Kumar Nandicoori

    Signal Transduction Laboratory, National Institute of Immunology, New Delhi, India
    For correspondence
    vinaykn@nii.ac.in
    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 Biotechnology , Ministry of Science and Technology (BT/PR13522/COE/34/27/2015)

  • Vinay Kumar Nandicoori

University Grants Commission (DS Kothari Postdoctoral Fellowship)

  • Savita Lochab

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

Ethics

Animal experimentation: The experimental protocol for the animal experiments was approved by the Animal Ethics Committee of the National Institute of Immunology, New Delhi, India. The approval (IAEC#409/16 & IAEC#462/18) is as per the guidelines issued by Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Received: August 29, 2019
  2. Accepted: March 27, 2020
  3. Accepted Manuscript published: March 30, 2020 (version 1)
  4. Version of Record published: April 16, 2020 (version 2)
  5. Version of Record updated: May 27, 2020 (version 3)

Copyright

© 2020, Lochab 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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  1. Savita Lochab
  2. Yogendra Singh
  3. Sagar Sengupta
  4. Vinay Kumar Nandicoori
(2020)
Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome
eLife 9:e51466.
https://doi.org/10.7554/eLife.51466
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