结核分枝杆菌抑制宿主 DNA 修复以提高其细胞内存活率,Cell Host & Microbe

结核分枝杆菌( Mtb ) 会引发巨噬细胞的明显变化，从而形成作为营养源的脂滴。我们发现Mtb通过抑制 DNA 修复反应来促进脂滴的形成，从而激活 I 型 IFN 通路和清道夫受体 A1 (SR-A1) 介导的脂滴形成。细菌脲酶 C (UreC、Rv1850) 通过与 RuvB 样蛋白 2 (RUVBL2) 相互作用并阻止 RUVBL1-RUVBL2-RAD51 DNA 修复复合物的形成来抑制宿主 DNA 修复。抑制该修复途径会增加微核的丰度，从而触发环 GMP-AMP 合酶 (cGAS)/干扰素基因刺激剂 (STING) 途径以及随后的干扰素-β (IFN-β) 产生。UreC 介导的 IFN-β 通路激活上调 SR-A1 的表达，形成脂滴，促进Mtb复制。通过脲酶抑制剂抑制 UreC 会损害巨噬细胞内和体内Mtb的生长。因此，我们的研究结果确定了结核分枝杆菌触发一系列细胞事件的机制，从而建立营养丰富的复制生态位。

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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.