CsoR Is Essential for Maintaining Copper Homeostasis in <i>Mycobacterium tuberculosis</i>

Mycobacterium tuberculosis, a pathogen infecting one third of the world population, faces numerous challenges within the host, including high levels of copper. We have previously shown that M. tuberculosis CsoR is a copper inducible transcriptional regulator. Here we examined the hypothesis that csoR is necessary for maintaining copper homeostasis and surviving under various stress conditions. With an unmarked csoR knockout strain, we were able to characterize the role of csoR in M. tuberculosis as it faced copper and host stress. Growth under high levels of copper demonstrated that M. tuberculosis survives copper stress significantly better in the absence of csoR. Yet under minimal levels of copper, differential expression analysis revealed that the loss of csoR results in a cell wide hypoxia-type stress response with the induction of the DosR regulon. Despite the stress placed on M. tuberculosis by the loss of csoR, survival of the knockout strain was increased compared to wild type during the early chronic stages of mouse infection, suggesting that csoR could play an active role in modulating M. tuberculosis fitness within the host. Overall, analysis of CsoR provided an increased understanding of the M. tuberculosis copper response with implications for other intracellular pathogens harboring CsoR.结核分枝杆菌（Mycobacterium tuberculosis）是感染全球三分之一人口的病原体，在宿主体内会面临多重胁迫，其中便包括高浓度铜离子环境。我们此前的研究证实，结核分枝杆菌的CsoR属于铜诱导型转录调节因子。本研究旨在验证“csoR基因对于维持铜稳态以及在多种胁迫条件下存活不可或缺”这一假说。我们通过构建无标记csoR敲除菌株，表征了csoR在结核分枝杆菌应对铜胁迫与宿主胁迫过程中的功能。高浓度铜离子环境下的生长实验显示，缺失csoR的结核分枝杆菌对铜胁迫的耐受性显著提升。而在低浓度铜离子环境中，差异表达分析结果表明，csoR的缺失会引发全细胞缺氧型胁迫响应，诱导DosR调节子的表达。尽管csoR的缺失会给结核分枝杆菌带来胁迫压力，但在小鼠感染的早期慢性阶段，敲除菌株的存活率相较于野生型菌株有所升高，这提示csoR可能在调节结核分枝杆菌在宿主体内的适合度中发挥主动作用。综上，对CsoR的研究加深了我们对结核分枝杆菌铜响应机制的认知，这一发现对于其他携带CsoR的胞内病原体亦具有参考价值。