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Dynamic Regulation of Epithelial Cell Survival by Enteropathogenic E. coli

致病性大肠杆菌对上皮细胞存活的动态调节

基本信息

批准号：
8443543
负责人：
V K VISWANATHAN
金额：
$ 1.08万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443543
关键词：
5 year old A Mouse Ablation Animal Model Apoptotic Bacteria Bacterial Proteins Brush Border Cell Communication Cell Death Cell Survival Cells Cessation of life Child Citrobacter rodentium Complement Cytochromes Cytosol Data Developing Countries Diarrhea Disease Enterocytes Epithelial Cells Future Goals Human In Vitro Infection Intervention Intestines Lead Mass Spectrum Analysis Measures Mediating Methods Mitochondria Morbidity - disease rate Mus Mutagenesis Organism Oryctolagus cuniculus Pathogenesis Pathway interactions Phase Phenotype Phosphorylation Play Process Proteins Proteomics Regulation Reporting Role Signal Pathway Signal Transduction Small Interfering RNA Syringes Testing Transgenic Mice Transgenic Organisms Type III Secretion System Pathway Vaccines Virulence Virulence Factors Yeasts cellular microvillus enteropathogenic Escherichia coli extracellular mortality mutant pathogen premature prevent therapeutic target yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Enteropathogenic E. coli (EPEC), an intestinal pathogen that causes diarrhea, is responsible for significant morbidity and mortality, especially among children below 5 years of age in developing countries. The precise mechanism(s) by which EPEC causes diarrhea is currently not known. The bacteria elaborate a syringe-like type III secretion system that delivers key virulence factors directly into host intestinal epithelial cells. During the initial phase of infection, EPEC appears to specifically limit the death of the underlying epithelial cells. The focus of this proposal is the suppression of host cell death by the type III-secreted protein EspZ, which is unique to EPEC and related pathogens. Strains lacking EspZ are highly impaired for colonization and disease in animal models of infection. We hypothesize that EspZ interacts with host proteins to suppress premature death of infected enterocytes and, thereby, plays a key role in intestinal colonization by A/E pathogens. We propose to (1) validate the interaction of EspZ with host cell partners, define EspZ interaction domains, and generate specific EspZ mutants deficient for interaction(s), (2) characterize the role of EspZ and its interaction partners in activating signaling pathways that contribute to the survival of host cells, and (3) define the role of EspZ and its interaction partners in pathogenesis using animal models of infection. Understanding the key role of EspZ, and of host survival to pathogenesis, could lead to future efforts to inhibit EspZ function, and thereby control EPEC-associated diarrhea.

描述（由申请人提供）：肠病性大肠杆菌 (EPEC) 是一种引起腹泻的肠道病原体，是造成重大发病率和死亡率的原因，特别是在发展中国家 5 岁以下儿童中。目前尚不清楚 EPEC 引起腹泻的确切机制。这种细菌精心设计了一种类似注射器的 III 型分泌系统，可将关键毒力因子直接输送到宿主肠上皮细胞中。在感染的初始阶段，EPEC 似乎特别限制了底层上皮细胞的死亡。该提案的重点是通过 III 型分泌蛋白 EspZ 抑制宿主细胞死亡，该蛋白是 EPEC 和相关病原体所独有的。缺乏 EspZ 的菌株在感染动物模型中的定植和疾病严重受损。我们假设 EspZ 与宿主蛋白相互作用，抑制受感染肠上皮细胞的过早死亡，从而在 A/E 病原体的肠道定植中发挥关键作用。我们建议（1）验证EspZ与宿主细胞伙伴的相互作用，定义EspZ相互作用域，并生成缺乏相互作用的特定EspZ突变体，（2）表征EspZ及其相互作用伙伴在激活有助于宿主细胞生存的信号通路中的作用，以及（3）使用感染动物模型定义EspZ及其相互作用伙伴在发病机制中的作用。了解 EspZ 以及宿主生存对发病机制的关键作用，可能会导致未来努力抑制 EspZ 功能，从而控制 EPEC 相关腹泻。