<i>Mycobacterium tuberculosis</i> exploits host ATM kinase for survival advantage through SecA2 secretome.

Abstract

(<i>Mtb</i>) produces inflections in the host signaling networks to create a favorable milieu for survival. The virulent <i>Mtb</i> strain, <i>Rv</i> caused double strand breaks (DSBs), whereas the non-virulent <i>Ra</i> 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 <i>Rv</i> activates ATM-Chk2 pathway of DNA damage response (DDR) signaling, resulting in altered cell cycle. Instead of the classical ATM-Chk2 DDR, <i>Mtb</i> gains survival advantage through ATM-Akt signaling cascade. Notably, in vivo infection with <i>Mtb</i> led to sustained DSBs and ATM activation during chronic phase of tuberculosis. Addition of ATM inhibitor enhances isoniazid mediated <i>Mtb</i> 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 <i>Mtb</i> provides survival niche through activation of ATM kinase.