Peptide effectors of virulence factor production in Vibrio cholerae

描述（由申请人提供）：霍乱弧菌是一种革兰氏阴性病原体，可引起使人衰弱的腹泻疾病，每年影响约5-10万人。霍乱弧菌引起流行病的能力依赖于体内基因的协调表达。最近的研究表明，许多霍乱弧菌基因在体内是暂时表达的。例如，编码产生霍乱毒素和毒素协同调节菌毛的基因在感染早期被诱导，但在离开宿主之前被抑制。其他基因在感染早期被抑制，在感染后期被诱导。霍乱研究的一个关键问题是这些基因在体内是如何调控的。群体感应被认为是体内基因协调调节的一种模式。然而，群体感应模型的一个主要缺点是它不能解释广泛存在的群体感应阴性流行菌株的晚期基因调控。在这个应用程序中，我们提出的初步数据表明，环肽作为群体感应独立信号的功能，影响毒力基因调控。我们提出两个具体目标来扩展这些初步发现。在目标1中，我们将确定毒力因子产生的有效环肽抑制剂，并表征它们对毒力基因表达的影响。在目标2中，我们将测试肽抑制剂是否在体内起作用。这些目标的完成将证实环肽在毒力基因表达中的作用，并为感染过程中基因调控提供新的机制。

DESCRIPTION (provided by applicant): Vibrio cholerae is a Gram-negative pathogen that causes a debilitating diarrheal disease that affects an estimated 5-10 million people each year. The ability of V. cholerae to cause epidemic disease is dependent on the coordinated expression of genes in vivo. Recent work has shown that many V. cholerae genes are temporally expressed in vivo. For example the genes encoding for the production of cholera toxin and the toxin coregulated pilus are induced early in infection, but repressed prior to exiting the host. Other genes are repressed early in infection and induced late in infection. One of the key questions in cholera research is how these genes are regulated in vivo. Quorum sensing has been proposed as a model for coordinate regulation of genes in vivo. However, a major shortcoming of the quorum-sensing model is that it fails to explain late gene regulation in widespread quorum sensing negative epidemic strains. In this application we present preliminary data to show that cyclic peptides function as quorum sensing independent signals that effect virulence gene regulation. We propose two specific aims to expand on these preliminary findings. In Aim 1 we will identify potent cyclic peptide inhibitors of virulence factor production and characterize their effects on virulence gene expression. In Aim 2 we will test whether the peptide inhibitors function in vivo. The completion of these aims will confirm the role of cyclic peptides in virulence gene expression and provide a novel mechanism for gene regulation during infection.