purA通过调控cAMP-CRP通路影响沙门氏菌肠道定植的机制研究

沙门氏菌在肠道的定植不但危害宿主健康，还可能促进耐药基因传播，严重威胁公共卫生安全。靶向沙门氏菌定植过程开发去定植药物成为新的研究热点。因此，发掘调控细菌肠道定植的新靶点，解析其作用机制对去定植药物开发具有重要意义。我们前期研究发现purA基因对沙门氏菌肠道定植具有重要调控作用，但具体机制尚不清楚。部分实验结果表明其调控作用可能与环腺苷酸（cAMP）及其受体蛋白（CRP）有关，因此我们提出‘purA通过cAMP-CRP复合物调控沙门氏菌Ⅲ型分泌系统（T3SS）中定植关键基因的转录协助细菌定植’这一科学假设。本项目拟利用细胞感染模型，结合分子生物学与组学手段研究沙门氏菌中cAMP-CRP响应purA对细菌定植能力的调控，挖掘沙门氏菌T3SS中受purA-cAMP-CRP通路调控的具体基因，最终阐明purA通过CRP介导沙门氏菌定植的调控网络，为靶向purA开发去定植药物提供理论基础。

The Salmonella spp. colonized in host intestine are deemed as one of greatest challenges to the public health not only because their pathogenicity but also their active roles in transmission and evolution of antibiotic resistance genes among bacteria. Therefore, accumulative investigations focus on the decolonization approaches to reduce the colonization of Salmonella spp. in host intestine with much lower selective pressure. It is notable that to explore more modulators for intestinal colonization as well as their relative modes of action will benefit the development of decolonization approaches against Salmonella infection. Our previous findings revealed that purA acts as an essential role in the progress of intestinal colonization of Salmonella spp., but its regulatory mechanisms stay unclear. As suggested by the results so far, the modulation of purA is hypothesized to functionalize the Salmonella type III secretion system (T3SS) via bacterial cAMP-CRP pathway. To validate our hypothesis, the current project will investigate the impact of cAMP-CRP complex on colonizing capability of Salmonella in response to the purA gene. Moreover, the downstream T3SS related genes under regulation of purA-cAMP-CRP pathway will be screened and unveiled with both multi-omics and molecular biology methods. This project will explain the regulation network controlled by purA for bacterial colonization in depth and is expected to provide the solid underpinnings for purA as a potential target in development of decolonization approaches against Salmonella infection.