SIGNALING MECHANISMS IN VIBRIO CHOLERAE PARALLEL QUORUM SENSING PATHWAYS

 描述(申请人提供)：霍乱弧菌是霍乱疾病的病原体，通过群体感应(QS)调节毒力因子的产生、生物膜的形成、能力和其他重要过程，群体感应(QS)是一种细胞间通信机制，依赖于被称为自身诱导剂的化学信号分子的产生、检测和反应。QS允许细菌协调整个种群的基因表达，并作为协调的基团发挥作用。除了两个典型的QS信号通路外，我们还发现两个额外的化学感受器整合到霍乱弧菌的中央QS回路中。重要的是，我们发现，这四条感官通路的破坏共同导致霍乱弧菌无法在动物宿主上定居。我们的数据还表明，这两个新鉴定的受体检测到某些未知的胞外分子，不同于两个已知的自身诱导剂，即AI-1和AI-2。在目标1中，我们将对这两个新的信号分子进行鉴定和表征。我们还将确定这些信号的生物合成途径。在目标2中，我们将定义这两个新受体的信号检测机制。在目标3中，我们将确定每个单独的QS受体在体内毒力基因表达中的贡献。总之，我们的工作不仅将确定qs在霍乱弧菌致病过程中的作用，还将阐明多种信号的整合如何在细菌细胞间通信过程中产生一致的反应。现在已经确定，QS被许多细菌物种利用来调节有害和有益的性状。该领域的一个长期目标是开发前QS和/或反QS分子来操纵细菌的群体行为。我们希望利用QS方面的知识来设计干预策略，这些策略可以转化为对抗传染病的新疗法。

 DESCRIPTION (provided by applicant): 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. In addition to the two canonical QS signaling pathways, we discovered that two additional chemical sensory receptors 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 these two newly identified receptors detect certain unidentified extracellular molecules different from the two known autoinducers, CAI-1 and AI-2. In Aim 1, we will identify and characterize these two new signal molecules. We will also determine the biosynthetic pathways for these signals. In Aim 2, we will define the signal detection mechanisms for these two new receptors. In Aim 3, we will determine the contribution from each individual QS receptor in virulence gene expression in vivo. 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.