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.

中文翻译：

---

结核分枝杆菌利用宿主ATM激酶通过SecA2分泌组获得生存优势

结核分枝杆菌（Mtb）在宿主信号网络中产生拐点，从而为生存创造了有利的环境。有毒的Mtb菌株Rv引起双链断裂（DSB），而无毒的Ra菌株触发单链DNA产生。SecA2途径分泌的效应子对于DSBs的产生是必不可少的。通过Rv介导的DSB的积累会激活DNA损伤反应（DDR）信号转导的ATM-Chk2途径，从而导致细胞周期改变。与传统的ATM-Chk2 DDR相比，Mtb通过ATM-Akt信号级联获得了生存优势。值得注意的是，在体内与感染在结核病的慢性期，Mtb导致持续的DSB和ATM活化。在巨噬细胞和鼠类感染模型中，添加ATM抑制剂可增强异烟肼介导的Mtb清除，表明其可用于宿主定向辅助治疗。总体而言，数据表明，由Mtb的SecA2分泌基因组造成的DSB通过激活ATM激酶提供了生存环境。