PATHOGENIC MECHANISMS IN UTI

据估计，全球每年发生1.5亿例尿路感染，直接卫生保健费用超过60亿美元，使尿路感染成为一个非常重大的公共卫生负担。本项目提出的研究将提高我们对尿路感染的流行病学、微生物生态学、分子发病机制和预防的认识。该项目的目标将通过发展一个多学科研究小组来实现，该小组将合作开展四个相互关联的项目。项目1将进行一项双盲安慰剂对照试验，以确定一种crispatis阴道益生菌是否会降低女性复发性尿路感染的发生率。该试验还将研究益生菌菌株对受试者阴道上皮细胞的粘附性，从而深入了解所涉及的宿主和微生物机制。项目2将解决以下假设：膀胱和阴道上皮细胞表面鞘糖脂在结构上被组织成称为小泡的多营养质膜组件，并且小泡参与对尿路致病性大肠杆菌的附着和摄取的初始上皮反应。项目3将采用在上一个资助期间开发的两种新技术。即高密度微阵列和全基因组突变扫描，在基因组水平上表征尿路致病性大肠杆菌菌株在复发性尿路感染过程中以及从无症状到有症状感染转变过程中的分子适应。该项目还将确定这种适应性进化如何影响尿路病原体结合和侵入上皮细胞的能力，并诱导炎症

An estimated 150 million UTIs occur annually on a global basis, accounting for direct health care costs exceeding 6 billion dollars and making UTIs a very significant public health burden. This program project proposes studies that will improve our understanding of the epidemiology, microbial ecology, molecular pathogenesis and prevention of UTIs. The objectives of the project will be met through the development of a multidisciplinary research team that will collaborate to carry out four interrelated projects. Project 1 will undertake a double-blind placebo-controlled trial to determine whether a Lactobacillus crispatis vaginal probiotic will reduce the incidence of recurrent UTIs in women. The trial will also study adherence of the probiotic strain to vaginal epithelial cells from the subjects and will thus provide insight into the host and microbial mechanisms involved. Project 2 will address the hypothesis that cell surface glycosphingolipids in the bladder and vaginal epithelium are structurally organized into pleotrophic plasma membrane assemblies called caveolae and that caveolae participate in the initial epithelial response to attachment and uptake of uropathogenic e. coil Project 3 will employ two novel technologies that were developed during the previous funding period, namely high density microarrays and whole genome mutation scanning to characterize on a genomic level the molecular adaptation that uropathogenic E. coil strains undergo in the course of recurrent UTIs and in shifting from an asymptomatic to symptomatic infection. The project will also define how such adaptive evolution affects the ability of uropathogens to bind and invade epithelial cells, induce inflammation and resist phagocytosis. In Project 4, the association of host susceptibility to recurrent cystitis or pyelonephritis with known or novel mutations in specifically selected candidate host genes will be examined. The candidate genes to be studied are toll-like receptors (TLR2, TLR4, and TLR6), chemokine receptors (CXCRI and CXCR2), and interferon y receptors (IFN-yR1 and IFN-yR2). A laboratory core will provide microbiological studies, primary bladder and vaginal epithelial cells, characterization of urovirulence genes, bacterial adherence assays and other resources to the projects. An Administrative/Biostatistical Core will coordinate the overall project and provide biostatistical expertise to all investigators. The proposed studies will result in an improved understanding of pathogenetic mechanisms in UTIs and will result in new approaches to prevention of UTIs.