Signaling Mechanisms in Vibrio Cholerae Parallel Quorum Sensing Pathways

项目摘要 人类霍乱弧菌，霍乱的病原体，调节 毒力因子的产生、生物膜的形成、能力等重要过程 通过群体感应(QS)，一种依赖于生产的细胞-细胞通信机制， 检测和对化学信号分子的反应称为自体诱导剂。QS允许细菌 协调整个种群的基因表达，并作为协调的群体发挥作用。我们有 确定了四条整合到霍乱弧菌中央QS回路的QS信号通路。 重要的是，我们发现这四条感官通路的破坏共同导致了V。 霍乱弧菌不能在动物宿主上定居。我们的数据还表明，乙醇胺和环状 AMP(CAMP)分别负责控制其中两个受体CqsR和VPSS。 在目标1中，我们将确定乙醇胺和其他相关分子如何调节CqsR。在AIM 2，我们将确定cAMP如何调节VPS。在目标3中，我们将定义监管层级 在霍乱弧菌QS循环中。具体地说，我们将确定最近发现的 在qs基因调控中，环二核苷酸称为环GMP-AMP。共同努力，我们的工作不仅将 明确qs在霍乱弧菌致病中的作用，它还将说明多个 信号在细菌细胞间的通讯过程中产生一致的反应。现在是时候了 众所周知，QS被许多细菌物种利用来调节有害和 有益的特征。该领域的一个长期目标是开发亲QS和/或反QS分子 操纵细菌的群体行为。我们希望利用QS方面的知识来实现 设计可转化为抗击传染性疾病的新疗法的干预策略 疾病。

Project Summary The human pathogen Vibrio cholerae, the causative agent of the disease cholera, regulates virulence factor production, biofilm formation, competence, and other important processes through quorum sensing (QS), a cell-cell communication mechanism that relies on the production, detection, and response to chemical signal molecules called autoinducers. QS allows bacteria to coordinate population-wide gene expression and function as coordinated groups. We have identified four QS signaling pathways that integrate into the central QS circuit of V. cholerae. Importantly, we found that disruption of these four sensory pathways altogether renders V. cholerae unable to colonize animal hosts. Our data also suggest that ethanolamine and cyclic AMP (cAMP), respectively, are responsible for controlling two of these receptors, CqsR and VpsS. In Aim 1, we will determine how ethanolamine and other related molecules regulate CqsR. In Aim 2, we will determine how cAMP regulates VpsS. In Aim 3, we will define the regulatory hierarchy in the V. cholerae QS circuit. Specifically, we will determine the roles of a recently discovered cyclic dinucleotide called cyclic GMP-AMP in QS gene regulation. Together, our work will not only define the role of QS in V. cholerae pathogenesis, it will also illustrate how integration of multiple signals results in a coherent response in a bacterial cell-cell communication process. It is now well established that QS is employed by many bacterial species to regulate both harmful and beneficial traits. A long standing goal in the field is to develop pro-QS and/or anti-QS molecules to manipulate bacterial group behaviors. Our hope is to harness the knowledge on QS to enable the design of interference strategies that can be translated into new therapies to combat infectious diseases.