Quorum sensing regulation of bacterial development

项目摘要 细菌使用称为群体感应的细胞-细胞信号系统进行交流，集体改变 基因表达对细胞密度变化的反应。仲裁感知控制有益于 适应和生存组，包括生物膜形成、运动性、生物发光和毒力因子 分泌物。调节群体感应的分子有可能用作针对以下目标的抗微生物药物 使用群体感应来控制毒力的细菌。因此，迫切需要全面地 了解细胞-细胞信号如何调节毒力并影响细菌在其环境中的地位。 尽管在阐明法定信号输入方面取得了进展，但对输出的了解相对较少。 控制群体行为的转录调控程序。我的研究目的是 定义细菌如何使用群体感应信号来控制毒力基因的表达。为了实现这个目标，我们 研究弧菌的群体感应基因调控，作为相关病原体和已建立的群体 感测模型系统。群体感应首先在生物发光弧菌中被阐明，这些细菌 系统现在是人类群体感应通道的特殊模型。 霍乱弧菌、创伤弧菌和副溶血性弧菌。在弧菌中，毒力基因 表达受群体感应中心的LuxR型主转录因子控制 路径。我的工作表明，群体感应和LuxR激活和抑制了数百个基因 对影响细胞生长和生理的法定信号的反应。我的实验室将扩大这个基金会 在接下来的五年里，在群体感应和基因表达之间建立联系。我们有 发现了LuxR与核样相关蛋白协同进行基因调控的新机制 对群体感应基因的精确计时和表达水平至关重要。我的实验室将把这项工作扩展到 确定致病弧菌中枢性LuxR/HapR蛋白的调控机制是关键 开发群体感应抑制剂的目标。此外，我们还证明了群体感应途径 与其他信号通路相交(例如，渗透胁迫反应通路)。我们将使用时态的，单一的- 细胞和种群水平的实验，以研究基因表达是如何协调的，以响应 生长和寄主定植过程中的细胞密度和局部环境。最后，我们现在正在扩展 我们检查群体感应基因调控的知识和方法 分枝杆菌，包括流行的人类病原体结核分枝杆菌。我们已经发起了 鉴定分枝杆菌群体感应基因网络及其对毒力影响的研究 表型。总体而言，这项工作将提供对理解法定信令和 它如何影响细菌的发病机制，以促进未来疾病治疗的进展。

Project Summary Bacteria communicate using the cell-cell signaling system called quorum sensing to collectively alter gene expression in response to changes in cell density. Quorum sensing controls behaviors that benefit the group for adaption and survival, including biofilm formation, motility, bioluminescence, and virulence factor secretion. Molecules that modulate quorum sensing have potential use as anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence. Thus, there is a critical need to comprehensively understand how cell-cell signaling regulates virulence and impacts bacteria in their environmental niches. Despite advances in elucidating the quorum signaling inputs, comparatively less is known about the output – the transcriptional regulation program that controls group behaviors. The objective of my research is to define how bacteria use quorum sensing signaling to control virulence gene expression. Toward this goal, we study quorum sensing gene regulation in Vibrios, both as relevant pathogens and as established quorum sensing model systems. Quorum sensing was first elucidated in bioluminescent Vibrios, and these bacterial systems now serve as exceptional models for the quorum sensing pathways that are mirrored in the human pathogens Vibrio cholerae, Vibrio vulnificus, and Vibrio parahaemolyticus. In Vibrios, virulence gene expression is controlled by the LuxR-type master transcription factors at the center of the quorum sensing pathway. My work has shown that quorum sensing and LuxR activate and repress hundreds of genes in response to quorum signals that impinge on cell growth and physiology. My lab will expand this foundation over the next five years to establish links between quorum sensing and gene expression. We have uncovered novel mechanisms of gene regulation by LuxR in concert with nucleoid-associated proteins that are critical for precise timing and expression levels of quorum sensing genes. My lab will extend this work by determining the regulatory mechanism of the central LuxR/HapR proteins in pathogenic Vibrios, which are key targets for developing inhibitors of quorum sensing. Further, we have shown that the quorum sensing pathway intersects other signaling pathways (e.g., the osmotic stress response pathway). We will use temporal, single- cell, and population-level experiments to study how gene expression is coordinated in response to changes in both cell density and the local environment during growth and host colonization. Finally, we are now extending our knowledge and methodological approaches to examine quorum sensing gene regulation in the Mycobacteria, which includes the prevalent human pathogen Mycobacterium tuberculosis. We have initiated studies to identify the quorum sensing gene network in Mycobacteria and determine its impact on virulence phenotypes. Overall, this work will provide the fundamental data critical to understanding quorum signaling and how it impacts bacterial pathogenesis to contribute to future advances in disease treatment.