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，可引起一种使人衰弱的腹泻病，估计每年影响500 - 1000万人。霍乱弧菌引起流行病的能力依赖于体内基因的协调表达。最近的工作表明，许多霍乱弧菌基因在体内暂时表达。例如，编码产生霍乱毒素和毒素共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，在感染晚期被诱导。霍乱研究中的一个关键问题是这些基因在体内是如何调节的。群体感应已被提出作为体内基因协调调控的模型。然而，群体感应模型的一个主要缺点是，它不能解释广泛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，我们提出了初步的数据表明，环肽作为群体感应独立的信号，影响毒力基因的调控。我们提出了两个具体目标，以扩大这些初步调查结果。在目标1中，我们将确定有效的环肽抑制剂的毒力因子的生产和表征其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，并为感染过程中的基因调控提供新的机制。 公共卫生相关性：拟议的研究将确定作为霍乱弧菌毒力因子生产抑制剂的肽。这些肽的鉴定将促进我们对霍乱弧菌如何引起疾病的理解，并可能确定一种新的方法来限制霍乱弧菌在暴发期间的传播。

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. PUBLIC HEALTH RELEVANCE: The proposed research will identify peptides that function as inhibitors of virulence factor production in Vibrio cholerae. Identification of these peptides will advance our understanding of how Vibrio cholerae causes disease and may identify a novel method to limit the spread of V. cholerae during outbreaks.