Quorum sensing regulation of bacterial development

项目摘要 细菌利用称为群体感应的细胞间信号系统进行交流， 基因表达对细胞密度变化的反应。群体感应控制的行为有利于 适应和存活组，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具有作为抗微生物药物的潜在用途， 利用群体感应来控制毒性的细菌。因此，迫切需要全面 了解细胞-细胞信号传导如何调节毒力并影响环境中的细菌。 尽管在阐明群体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。我研究的目的是 定义细菌如何使用群体感应信号来控制毒力基因的表达。为了实现这一目标，我们 研究弧菌中的群体感应基因调控，既作为相关病原体又作为既定群体 传感模型系统群体感应首先在生物发光弧菌中阐明，这些细菌 系统现在作为群体感应途径的特殊模型， 病原体霍乱弧菌、创伤弧菌和副溶血性弧菌。在弧菌中， 表达由位于群体感应中心的LuxR型主转录因子控制 通路我的工作表明，群体感应和LuxR激活和抑制数百个基因， 对影响细胞生长和生理的群体信号的反应。我的实验室将扩大这个基础 在接下来的五年里，建立群体感应和基因表达之间的联系。我们有 揭示了LuxR与类核蛋白相关的基因调控的新机制， 对于群体感应基因的精确时间和表达水平至关重要。我的实验室将通过 确定致病性弧菌中中心LuxR/HapR蛋白的调节机制，这是关键 开发群体感应抑制剂的目标。此外，我们已经表明，群体感应途径， 与其它信号通路相交（例如，渗透胁迫反应途径）。我们将使用时间，单一- 细胞和群体水平的实验，以研究基因表达是如何协调的变化， 生长和宿主定殖期间的细胞密度和局部环境。最后，我们现在将 我们的知识和方法来研究群体感应基因的调控， 分枝杆菌，包括流行的人类病原体结核分枝杆菌。我们已开始 鉴定分枝杆菌群体感应基因网络并确定其对毒力影响的研究 表型总的来说，这项工作将提供理解群体信号的关键基础数据， 它如何影响细菌发病机制，以促进疾病治疗的未来进展。

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.