毒力
生物
DNA损伤
效应器
激酶
细胞生物学
蛋白激酶B
检查点激酶2
结核分枝杆菌
信号转导
DNA
蛋白激酶A
肺结核
丝氨酸苏氨酸激酶
遗传学
基因
医学
病理
作者
Savita Lochab,Yogendra Singh,Sagar Sengupta,Vinay Kumar Nandicoori
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2020-03-30
卷期号:9
被引量:10
摘要
(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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