TY - JOUR TI - Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome AU - Lochab, Savita AU - Singh, Yogendra AU - Sengupta, Sagar AU - Nandicoori, Vinay Kumar A2 - Garrett, Wendy S A2 - Kana, Bavesh D A2 - Lesley, Alasdair VL - 9 PY - 2020 DA - 2020/03/30 SP - e51466 C1 - eLife 2020;9:e51466 DO - 10.7554/eLife.51466 UR - https://doi.org/10.7554/eLife.51466 AB - (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. KW - Mycobacterium tuberculosis KW - DNA damage KW - SecA2 KW - ATM kinase KW - secretome KW - Akt JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -