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

• 批准号: 7916054
• 负责人: V K VISWANATHAN
• 金额: $ 25.21万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916054
• 关键词: 5 year old; Address; Apoptosis; Bacteria; Cell Death; Cell Survival; Cells; Cessation of life; Child; Developed Countries; Developing Countries; Diarrhea; Epithelial Cells; Flagellin; Future; In Vitro; Infection; Intestines; Lead; Mediating; Morbidity - disease rate; Pathogenesis; Pathway interactions; Phase; Pilum; Proteins; Regulation; Syringes; Type III Secretion System Pathway; Virulence Factors; abstracting; enteropathogenic Escherichia coli; in vivo; mortality; pathogen; plasma protein Z; premature

Abstract Enteropathogenic E. coli (EPEC) is a diarrheagenic pathogen that is responsible for significant morbidity and mortality, especially amongst children below 5 years of age in developing countries. The precise mechanism by which EPEC causes diarrhea is presently not known. The bacteria elaborate a syringe-like type III secretion system which conveys key virulence factors directly into host intestinal epithelial cells. EPEC also produces other virulence factors including flagellin and bundle-forming pili. During the initial phase of infection, EPEC appears to specifically limit the death of the underlying epithelial cells. Our initial studies show that a type III secreted protein EspZ (EPEC secreted protein Z), as well as flagellin, activate host survival pathways and inhibit apoptosis. While flagellin-dependent host cell survival has recently been explored with other pathogens, the mechanism by which EspZ, a protein unique to EPEC and related bacteria, suppresses host cell death pathways is not known. We propose to further explore the contribution of EspZ and flagellin to host intestinal epithelial cell survival both in vitro and in vivo, and to dissect the mechanism by which EspZ mediates its protective functions. Premature death of host cells can be detrimental to colonization and, therefore, these proteins are likely critical for EPEC pathogenesis. Understanding their mechanisms of action could lead to future efforts to inhibit their function, and thereby control EPEC pathogenesis.

摘要 肠致病性E.大肠杆菌（EPEC）是一种致病性病原体， 发病率和死亡率很高，特别是在5岁以下儿童中， 发展中国家EPEC引起腹泻的确切机制是 目前还不知道。这种细菌精心设计了一个类似于细菌的III型分泌系统 其将关键毒力因子直接传递到宿主肠上皮细胞中。EPEC 还产生其它毒力因子，包括鞭毛蛋白和形成鞭毛的皮利。期间 在感染的最初阶段，EPEC似乎特别限制了感染者的死亡。 下面的上皮细胞我们的初步研究表明，III型分泌蛋白EspZ (EPEC分泌蛋白Z）以及鞭毛蛋白激活宿主存活途径， 抑制细胞凋亡。虽然鞭毛蛋白依赖性宿主细胞的存活最近已经被证实， 与其他病原体一起探索，EspZ，一种独特的蛋白质， EPEC和相关细菌是否抑制宿主细胞死亡途径尚不清楚。我们 建议进一步探讨EspZ和鞭毛蛋白在宿主肠道中的作用， 上皮细胞存活在体外和体内，并剖析其机制， EspZ介导其保护功能。宿主细胞的过早死亡可能是 因此，这些蛋白质可能对EPEC至关重要 发病机制了解它们的作用机制，可有助于今后的努力， 抑制其功能，从而控制EPEC发病。