MECHANISM OF E. COLI INVASION OF THE RENAL PARENCHYMA

大肠杆菌侵入肾实质的机制

• 批准号: 3789990
• 负责人: MICHAEL DONNENBERG
• 金额: --
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3789990
• 关键词: Escherichia coli; aging; bacterial cytopathogenic effect; disease /disorder model; electron microscopy; epithelium; gentamicins; human old age (65+); human subject; human tissue; kidney infection; laboratory mouse; model design /development; mutant; nosocomial infections; nucleic acid hybridization; nucleic acid sequence; pyelonephritis; site directed mutagenesis; tissue /cell culture; urinalysis; urinary bladder epithelium; urinary catheterization; urinary incontinence; urinary tract infection; urinary tract obstruction; young adult human (21-34)

The urinary tract is the most common source of bacteremia in the elderly. Long-term urethral catheters constitute the greatest risk factor for bacteremia in chronic care facilities. E. coli is the leading cause of catheter-associated bacteremia in the elderly (as well as bacteremia unassociated with catheters). While much is known about factors associated with E. coli colonization of the urinary tract, the mechanisms by which this organism escapes the confines of the urinary tract lumen to enter the renal parenchyma and cause pyelonephritis are obscure. In order to study the mechanisms of E. coli renal invasion, an in vitro model of this process that utilizes human renal epithelial cells in tissue culture will be developed. The ability of E. coli to invade and to pass between or through these cells in comparison to control fecal isolates will be measured using well established assays. Inhibitors of epithelial and bacterial processes will be added to the model to identify those that are involved in renal invasion. Next, E. coli isolated from the urine of patients with various well-defined clinical syndromes will be compared to assess the contribution of renal invasive ability to pathogenicity. Epithelial cells from many individuals of different ages will be used to examine the effect of age on susceptibility to renal invasion. Finally, transposon mutagenesis of a virulent strain followed by in vitro and in vivo tests of invasion will be used to identify the genes involved in E. coli invasion of the kidney. These studies will provide important information on the mechanisms E. coli use to penetrate from the lumen of the urinary collecting system to the tissues of the kidney from where they can progress to the bloodstream and cause sepsis and death. Better comprehension of the process of renal invasion may lead to the development of strategies for prevention and intervention and may improve our understanding of the pathogenesis of invasive infections in general.

泌尿道是老年人菌血症最常见的来源。 长期留置导尿管是尿路感染的最大危险因素 慢性病护理机构中的菌血症。 大肠杆菌是导致 老年人导管相关菌血症（以及菌血症 与导管无关）。 虽然人们对相关因素了解很多 随着大肠杆菌在泌尿道定植，其机制 这种生物体逃离尿路管腔的限制进入 肾实质及肾盂肾炎的病因尚不清楚。 为了研究大肠杆菌肾侵袭的机制，体外培养 该过程的模型利用组织中的人肾上皮细胞 文化将得到发展。 大肠杆菌的侵入和通过能力 与对照粪便分离物相比，在这些细胞之间或通过这些细胞 使用完善的测定法进行测量。 上皮细胞抑制剂和 细菌过程将被添加到模型中以识别那些 参与肾侵犯。 接下来，从尿液中分离出大肠杆菌 患有各种明确临床综合征的患者将与 评估肾脏侵袭能力对致病性的贡献。 来自许多不同年龄个体的上皮细胞将被用于 检查年龄对肾侵犯易感性的影响。 最后， 强毒株的转座子诱变，然后进行体外和体内研究 体内入侵测试将用于鉴定大肠杆菌涉及的基因。 大肠杆菌侵入肾脏。 这些研究将提供有关大肠杆菌机制的重要信息 用于从泌尿收集系统的管腔渗透到 肾脏组织，从那里它们可以进入血液， 导致败血症和死亡。 更好地理解肾脏的过程 入侵可能导致制定预防和预防策略 干预并可能提高我们对发病机制的了解 一般侵袭性感染。