Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection.
Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection.
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DOI：
10.7554/elife.65351
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发表时间：
2021-05-18
期刊：
影响因子：
7.7
通讯作者：
Glickman MS
中科院分区：
文献类型：
--
作者：
Buglino JA;Sankhe GD;Lazar N;Bean JM;Glickman MS
感染吞噬细胞的细菌病原体必须部署感知和中和宿主杀菌效应器的机制。对于结核病的病原体结核分枝杆菌来说，这些机制使细菌能够迅速适应从气溶胶传播到肺泡巨噬细胞的初始生长。在这里，我们识别了结核分枝杆菌的一个分支信号通路，它通过RIP1膜内酶和PdtaS/R双组分系统的耦合活性对铜离子和一氧化氮的集成直接感应来控制肺内的生长。该电路使用双信号机制来灭活PdtaS/PdtaR双组分系统，该系统结构性地抑制毒力基因的表达。铜和NO通过N-末端GAF结构域中的二半胱氨酸基序抑制PdtaS传感器激酶。该途径的NO臂进一步受RIP1膜内酶控制的NO诱导的小RNA对PdtaR RNA结合反应调节因子的隔离控制。这个偶联的RIP1/PdtaS/PdtaR回路通过解除PdtaS/R介导的异腈白炭生物合成的抑制，控制NO抵抗和小鼠的急性肺部感染。这些研究确定了结核分枝杆菌感知和抵抗巨噬细胞化学效应物以实现致病的综合机制。
Bacterial pathogens that infect phagocytic cells must deploy mechanisms that sense and neutralize host microbicidal effectors. For Mycobacterium tuberculosis, the causative agent of tuberculosis, these mechanisms allow the bacterium to rapidly adapt from aerosol transmission to initial growth in the lung alveolar macrophage. Here, we identify a branched signaling circuit in M. tuberculosis that controls growth in the lung through integrated direct sensing of copper ions and nitric oxide by coupled activity of the Rip1 intramembrane protease and the PdtaS/R two-component system. This circuit uses a two-signal mechanism to inactivate the PdtaS/PdtaR two-component system, which constitutively represses virulence gene expression. Cu and NO inhibit the PdtaS sensor kinase through a dicysteine motif in the N-terminal GAF domain. The NO arm of the pathway is further controlled by sequestration of the PdtaR RNA binding response regulator by an NO-induced small RNA, controlled by the Rip1 intramembrane protease. This coupled Rip1/PdtaS/PdtaR circuit controls NO resistance and acute lung infection in mice by relieving PdtaS/R-mediated repression of isonitrile chalkophore biosynthesis. These studies identify an integrated mechanism by which M. tuberculosis senses and resists macrophage chemical effectors to achieve pathogenesis