Ethanolamine Signaling in Virulence Gene Regulation and Host/Microbial Interactions

毒力基因调控和宿主/微生物相互作用中的乙醇胺信号传导

• 批准号: 9262867
• 负责人: Melissa Kendall
• 金额: $ 38.89万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-11 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262867
• 关键词: Address; Adrenergic Agents; Assimilations; Bacterial Adhesins; Biochemical; Cells; Chemicals; Code; Complication; Data; Development; Disease; Disease Outbreaks; Dose; Enterocytes; Environment; Epidemiology; Epinephrine; Epithelial Cells; Escherichia coli EHEC; Escherichia coli O157:H7; Ethanolamines; Fimbrial Adhesins; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Hemolytic-Uremic Syndrome; Hemorrhagic colitis; Hormones; Human; In Vitro; Indigenous; Individual; Infection; Innate Immune System; Intervention; Intestines; Invaded; Kidney Failure; Large Intestine; Lead; Lesion; Life; Link; Location; Maps; Mediating; Metabolism; Microbe; Molecular; Nitrogen; Norepinephrine; Nutrient; Operon; Pathogenesis; Pathogenicity; Pathogenicity Island; Play; Production; Proteins; Regulation; Regulon; Research; Role; Shiga Toxin; Signal Transduction; Source; Symptoms; System; Transcriptional Regulation; Translating; Virulence; Work; cellular microvillus; commensal microbes; fitness; foodborne pathogen; gastrointestinal; gastrointestinal system; host-microbe interactions; microbiota; mutant; novel; pathogen; protein-histidine kinase; public health relevance; response; sensor; trait

 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.

 描述（由申请人提供）：大肠杆菌 O157: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症综合征 (HUS)，这是 EHEC 疾病的一种并发症，可导致肾衰竭。肠出血性大肠杆菌的感染剂量非常低，因此很难在流行病学上控制肠出血性大肠杆菌在大肠上的附着位置。 EHEC 还会产生导致 HUS 主要症状的志贺毒素。为了成功定植宿主并建立感染，EHEC 必须能够与本地微生物群竞争营养物质。 EHEC 在胃肠道中使用 EA 作为氮源，从而获得了相对于本地微生物群的竞争优势。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。对于EHEC的发病机制，我们对EutR基因在EHEC中的调控程度或EutR如何调节毒力基因知之甚少，在具体目标1中，我们将进行详细的研究。表征EutR在EHEC发病机制中的作用以及检查EutR毒力基因调节的机制，EutR对EA做出反应并调节eutR突变株中的毒力基因表达，这表明EHEC在特定目标2中编码第二个EA传感器。 ，我们将了解 EA 依赖性、EutR 独立毒力基因调控在 EHEC 中的作用和机制，具体目标 3 将如何解决这些问题。 EA 传感器有助于 EHEC 的适应度和感染期间毒力基因的表达，所提出的实验方法将更好地了解 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。制定干预和/或治疗肠出血性大肠杆菌疾病的独特策略。