Ethanolamine Signaling in Virulence Gene Regulation and Host/Microbial Interactions

 描述（由申请方提供）：大肠杆菌O 157：H7（EHEC）是一种食源性病原体，可在全世界引起血性腹泻和溶血性尿毒综合征（HUS），这是EHEC疾病的并发症，可导致肾衰竭。肠出血性大肠杆菌的感染剂量很低，因此很难进行流行病学控制。肠出血性大肠杆菌定植于大肠，附着于结肠上皮细胞，导致微绒毛消失。肠出血性大肠杆菌还产生滋贺毒素，引起溶血尿毒综合征的主要症状。为了成功地定殖宿主并建立感染，肠出血性大肠杆菌必须能够与本地微生物群竞争营养。乙醇胺（EA）存在于胃肠道中。肠出血性大肠杆菌使用EA作为氮源，从而获得了对土著微生物群的竞争优势。重要的是，肠出血性大肠杆菌已经将EA作为促进参与宿主定植和感染以及滋贺毒素产生的基因表达的信号。转录调节因子EutR激活编码EA代谢的基因的表达，并且我们确定EutR促进EHEC毒力基因的表达。虽然EutR是重要的EHEC的发病机制，很少有人知道EutR基因的调控程度EHEC或如何EutR的功能，以调节毒力基因。在具体目标1中，我们将详细描述EutR在EHEC发病机制中的作用，并研究EutR毒力基因调控的机制。有趣的是，肠出血性大肠杆菌响应EA和调节毒力基因表达的eutR突变株表明，肠出血性大肠杆菌编码的第二个EA传感器。在具体目标2中，我们将研究EHEC中依赖EA，不依赖EutR的毒力基因调控的作用和机制。具体目标3将解决如何这些EA传感器有助于肠出血性大肠杆菌的健身和毒力基因表达在感染过程中。所提出的实验方法将实现更好地理解EHEC激活其毒力基因的机制，并可能揭示EHEC发病机制的新方面。总之，这些数据可能会导致开发独特的策略干预和/或治疗肠出血性大肠杆菌病。

 DESCRIPTION (provided by applicant): Escherichia coli O157:H7 (EHEC) is a food-borne pathogen that causes bloody diarrhea and hemolytic uremic syndrome (HUS), a complication of EHEC disease that can lead to kidney failure, throughout the world. EHEC has a very low infectious dose, making it difficult to control epidemiologically. EHEC colonizes the large intestine where it attaches to colonic epithelial cells and causes effacement of microvilli. EHEC also produces Shiga toxin that causes the major symptoms of HUS. In order to successfully colonize the host and establish infection, EHEC must be able to compete with the indigenous microbiota for nutrients. Ethanolamine (EA) is present in the gastrointestinal tract. EHEC uses EA as a nitrogen source, thereby gaining a competitive advantage over the indigenous micriobiota. Importantly, EHEC has co-opted EA as a signal to promote expression of genes involved in host colonization and infection as well as in Shiga toxin production. The transcriptional regulator EutR activates expression of genes that code for EA metabolism, and we determined that EutR promotes expression of EHEC virulence genes. Although EutR is important for EHEC pathogenesis, very little is known concerning the extent of EutR gene regulation in EHEC or how EutR functions to regulate virulence genes. In Specific Aim 1, we will perform a detailed characterization of the role of EutR in EHEC pathogenesis as well as examine the mechanisms of EutR virulence gene regulation. Interestingly, EHEC responds to EA and modulates virulence gene expression in the eutR mutant strain suggesting that EHEC encodes a second EA sensor. In Specific Aim 2, we will investigate the roles and mechanisms of EA-dependent, EutR-independent virulence gene regulation in EHEC. Specific Aim 3 will address how these EA-sensors contribute to EHEC fitness and virulence gene expression during infection. The proposed experimental approaches will achieve a better understanding of mechanisms used by EHEC to activate its virulence genes and may reveal novel aspects of EHEC pathogenesis. Altogether, these data may lead to the development of unique strategies for intervention and/or treatment for EHEC disease.