PATHOGENIC MECHANISMS IN URINARY TRACT INFECTIONS

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An estimated 150 million UTIs occur annually on a global basis, accounting for direct health care costs of $6 billion. While no aggregate assessment of the morbidity, mortality and total costs related to UTIs can be calculated, these infections clearly represent a significant public health burden. This program project proposes studies that will improve our understanding of the epidemiology , risk factors, microbial ecology, molecular pathogenesis and prevention of UTIs. The objectives of the project will be met through the development of a multi-disciplinary research team that will collaborate to carry out four interrelated projects. Project 1 will delineate the protective role of hydrogen peroxide producing lactobacilli, the major microbial species of the normal vaginal flora, in preventing vaginal colonization with E. coli and UTI in young women. The project will ultimately test a novel approach to the prevention of UTI in women, namely, use of a highly adherent hydrogen peroxide producing lactobacillus strain administered as a vaginal suppository. In Project 2, the role and regulation of bladder epithelial cell glycosphingolipids as attachment sites for uropathogenic bacteria will be studied using primary cultures of bladder epithelial cells. Identification of specific interactions between bacterial adhesins and epithelial cell glycosphingolipid receptors may facilitate the development of novel means of prevention using topically applied comparative analogs. Project 3 will identify new virulence genes in two important uropathogens, E. coli and Pseudomonas aeruginosa by studying gene expression under conditions of actual infection. In Project 4, the epithelial cell responses and intracellular signaling pathways that are activated after Dr fimbria bearing E. coli attach to epithelial cells via Decay Accelerating Factor will be studied. A laboratory core will provide primary bladder epithelial cells, ribotyping, characterization of urovirulence genes and other resources to the projects. An Administrative/Biostatistical Core will coordinate the project and provide biostatistical expertise to project investigators. The proposed studies will result in new approaches to the prevention of UTIs.