Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival

• Published in: Cell host & microbe 2023-11, Vol.31 (11), p.1820-1836.e10
• Main Authors: Liu, Shanshan, Guan, Liru, Peng, Cheng, Cheng, Yuanna, Cheng, Hongyu, Wang, Fei, Ma, Mingtong, Zheng, Ruijuan, Ji, Zhe, Cui, Pengfei, Ren, Yefei, Li, Liru, Shi, Chenyue, Wang, Jie, Huang, Xiaochen, Cai, Xia, Qu, Di, Zhang, Haiping, Mao, Zhiyong, Liu, Haipeng, Wang, Peng, Sha, Wei, Yang, Hua, Wang, Lin, Ge, Baoxue
• Format: Article
• Language: English
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2023.09.010

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated activation of the IFN-β pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.