Quorum sensing regulation of EHEC virulence genes

EHEC毒力基因的群体感应调控

• 批准号: 7996624
• 负责人: VANESSA SPERANDIO
• 金额: $ 45.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996624
• 关键词: Binding; Complex; Development; Diarrhea; Disease; Disease Outbreaks; Dose; Epinephrine; Epithelial Cells; Escherichia coli EHEC; Escherichia coli O157; Event; Gene Expression Regulation; Genes; Genetic Transcription; Hemolytic-Uremic Syndrome; Hormones; Intervention; Intestines; Large Intestine; Lead; Lesion; Maps; Membrane; Norepinephrine; Pathogenesis; Phosphotransferases; Regulation; Regulon; Reporting; Role; Sensory; Shiga Toxin; Signal Transduction; Symptoms; System; Virulence; design; effective intervention; gastrointestinal; member; novel; protein protein interaction; quorum sensing; sensor

DESCRIPTION (provided by applicant): Enterohemorrhagic E. coli (EHEC) O157:H7 causes bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. EHEC has a very low infectious dose, making it difficult to control epidemiologically. EHEC colonizes the large intestine where it causes attaching and effacing (AE) lesions, and also produces Shiga toxins (Stx) that are responsible for the major symptoms of HUS. We recently reported that EHEC senses three signals to activate transcription of virulence genes: a bacterial aromatic autoinducer (AI-3) produced by the normal gastrointestinal flora, and the hormones epinephrine/norepinephrine produced by the host. These signals are detected by membrane bound sensor kinases that subsequently relay this information to a complex regulatory cascade to activate transcription of virulence genes. We have identified several members of this signaling cascade: the QseBC and QseEF two-component systems, and the QseA and QseD LysR-like regulators. However, many aspects of this regulatory cascade, which are crucial for EHEC virulence, remain poorly understood. This proposal represents a comprehensive effort to study the AI-3/epinephrine/norepinephrine signaling cascade, responsible for virulence gene regulation in EHEC. In Specific Aim 1, we will perform a detailed characterization of the QseBC regulon to map this complex regulatory network. In Specific Aim 2, we will characterize the protein-protein interactions between the QseA and QseD LysR-like regulators and their effect on gene regulation. Specific Aim 3 is designed to characterize the role of the novel QseEF two-component system in EHEC pathogenesis. The proposed experimental approaches will achieve a better understanding of the sensory events by which EHEC responds to activate its virulence genes, and may lead to the identification of other virulence genes and novel targets for the potential development of more effective intervention strategies for EHEC disease.

描述（由申请人提供）：肠内毛状大肠杆菌（EHEC）O157：H7在世界范围内引起血腥的腹泻和溶血性尿毒症综合征（HUS）。 EHEC的感染剂量非常低，因此很难通过流行病学控制。 EHEC在引起附着和esf efcac（AE）病变的大肠上殖民，还会产生志贺毒素（STX），负责HUS的主要症状。我们最近报道，EHEC感知了三个信号激活毒力基因的转录：正常胃肠道菌群产生的细菌芳族自动诱导剂（AI-3），以及宿主产生的激素肾上腺素/去甲肾上腺素。这些信号通过膜结合传感器激酶检测到，随后将此信息传递到复杂的调节级联反应以激活毒力基因的转录。我们已经确定了此信号级联的几个成员：QSEBC和QSEEF两个组件系统，以及QSEA​​和QSED LYSR样调节器。但是，这种监管级联对于EHEC毒力至关重要的许多方面仍然很少理解。该建议代表了研究AI-3/肾上腺素/去甲肾上腺素信号级联的全面努力，该级别负责EHEC中的毒力基因调节。在特定的目标1中，我们将对QSEBC调节器进行详细表征，以映射此复杂的调节网络。在特定的目标2中，我们将表征QSEA和QSED LYSR样调节剂之间的蛋白质 - 蛋白质相互作用及其对基因调节的影响。特定的目标3旨在表征新型QSEEF两组分系统在EHEC发病机理中的作用。所提出的实验方法将更好地理解EHEC对激活其毒力基因的反应的感觉事件，并可能导致鉴定其他毒力基因和新的靶标，以实现EHEC疾病的更有效干预策略的潜在发展。