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的最常见来源。 长期使用导尿管是最大的危险因素 慢性病护理设施中的菌血症。 E.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）。 虽然我们对与之相关的因素有很多了解， 用大肠大肠杆菌定植的泌尿道，其机制， 这种微生物会逃出泌尿道腔的限制， 肾实质不清而引起肾盂肾炎。 为了研究E.大肠杆菌肾浸润，体外 利用组织中的人肾上皮细胞的这一过程的模型 文化将得到发展。 E.大肠杆菌侵入并通过 与对照粪便分离物相比， 可以使用完善的测定法进行测量。 上皮细胞和 细菌过程将被添加到模型中，以确定那些 参与肾脏侵犯。 下一个E大肠杆菌从尿液中分离出来， 具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。 来自不同年龄的许多个体的上皮细胞将用于 研究年龄对肾脏受侵易感性的影响。 最后， 转座子诱变的毒力菌株，然后在体外和 体内侵袭试验将用于鉴定E. 大肠杆菌侵入肾脏。 这些研究将为E.杆菌 用于从尿液收集系统的内腔渗透到 肾脏组织，它们可以从那里进入血液， 导致败血症和死亡。 更好地理解肾脏疾病的过程 入侵可能会导致预防战略的发展， 干预，并可能提高我们对发病机制的理解， 一般来说是侵入性感染。