Environmental adaptation by Vibrio cholerae

项目摘要/摘要 霍乱是一种急性腹泻疾病，每年影响300-500万人。霍乱是一种IS 由革兰氏阴性菌霍乱弧菌引起，经常与流行病有关 疾病。霍乱弧菌是一种原产于水生生态系统的兼性人类病原体，可感染 人们通过饮用受污染的水或食物。霍乱弧菌一旦被摄取，就会在 小肠，在那里它产生一种毒素，导致脱水的分泌性腹泻，这种腹泻可能很快 致命的。霍乱的破坏性后果，加上它可以迅速传播和 它在水生生态系统中持续存在的能力，强调了开发新方法的必要性 与这种流行病作斗争。我们最近对霍乱弧菌的研究证明，多种药物外排 属于抗性-结瘤-分裂(RND)超家族的系统具有细胞外排功能 细胞中的代谢物。我们进一步表明，外排障碍会导致代谢物积累。 在细胞内，它们与周质感受器蛋白相互作用，启动适应性反应。这 包括激活ToxR导致LeuO转录增加和下调 毒力基因表达。然而，负责毒力抑制的代谢产物 仍然不为人所知。在这个提案中，我们将检验自动诱导器功能以启动 导致毒力抑制的适应性反应的表达。两个具体目标是 建议。第一个目的是研究ToxR和LeuO在细胞密度依赖基因中的功能 监管。第二个目标将调查RND介导的外流对适应性反应的贡献。 和殖民主义。确定调节V.的调节机制和环境线索。 霍乱弧菌的适应性反应将阐明霍乱弧菌致病机制的重要方面，提供一种 更好地了解导致疾病和流行病传播的因素，并突出新奇 抗击霍乱的方法。

PROJECT SUMMARY/ABSTRACT Cholera is an acute diarrheal disease that affects 3-5 million people each year. Cholera is an is caused by the Gram negative bacterium Vibrio cholerae and is frequently associated with epidemic disease. V. cholerae is a native to aquatic ecosystems and a facultative human pathogen that infects people through the consumption of contaminated water or food. Once ingested, V. cholerae colonizes the small intestine where it produces a toxin that causes a dehydrating secretory diarrhea that can be rapidly fatal. The devastating consequences of cholera, combined with the rapidity with which it can spread and its ability to persist in aquatic ecosystems, underscore the need for the development of novel approaches to combat this epidemic disease. Our recent studies in V. cholerae documented that multiple drug efflux systems belonging to the resistance-nodulation-division (RND) superfamily function to efflux cellular metabolites from the cell. We further showed that impaired efflux resulted in the metabolites accumulating intracellularly where they interacted with periplasmic sensor proteins to initiate adaptive responses. This included the activation of ToxR which resulted in increased leuO transcription and the downregulation of virulence gene expression. However, the metabolites that were responsible for virulence repression remain unknown. In this proposal we will test the hypothesis that auto-inducers function to initiate the expression of the adaptive responses that resulted in virulence repression. Two specific aims are proposed. The first aim will investigate the function of ToxR and LeuO in cell density-dependent gene regulation. The second aim will investigate the contribution of RND-mediated efflux to adaptive responses and colonization. Determining the regulatory mechanisms and environmental cues that modulate V. cholerae adaptive responses will illuminate important aspects of V. cholerae pathogenesis, provide a better understanding of the factors that contribute to disease and epidemic spread, and highlight novel approaches to combat cholera.