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.
- Vinay Kumar Nandicoori
- Savita Lochab
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Bavesh D Kana, University of the Witwatersrand, South Africa
© 2020, Lochab et al.
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