SIGNALING MECHANISMS IN VIBRIO CHOLERAE PARALLEL QUORUM SENSING PATHWAYS

 描述（由申请人提供）：人类病原体霍乱弧菌（霍乱的病原体）通过群体感应（QS）调节毒力因子产生、生物膜形成、感受态和其他重要过程，QS是一种细胞间通讯机制，依赖于对称为自诱导物的化学信号分子的产生、检测和响应。QS允许细菌协调群体范围内的基因表达，并作为协调群体发挥作用。除了两个典型的QS信号通路，我们发现两个额外的化学感觉受体整合到中央QS电路的V。重要的是，我们发现，这四种感觉通路的中断使霍乱弧菌无法在动物宿主中定植。我们的数据还表明，这两个新鉴定的受体检测某些未知的细胞外分子不同的两个已知的自诱导剂，CAI-1和AI-2。在目标1中，我们将鉴定和表征这两种新的信号分子。我们还将确定这些信号的生物合成途径。在目标2中，我们将定义这两种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在霍乱弧菌发病机制中的作用，还将说明多种信号的整合如何导致细菌细胞间通讯过程中的一致反应。现在已经确定，QS被许多细菌物种用来调节有害和有益的性状。本领域的长期目标是开发pro-QS和/或anti-QS分子以操纵细菌群体行为。我们希望利用QS知识来设计干扰策略，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.