Recurrent urinary tract infections (RUTI) affect millions of young women each year and result in substantial morbidity, time lost from work, and medical costs exceeding 10 million dollars per annum. Preliminary data suggest that young women with RUTI may be more likely to be nonsecretors of blood group antigens and that uroepithelial cells from nonsecretors (but not secretors) demonstrate 2 unique surface-exposed glycosphingolipids (GSLs), sialosyl gal-globoside (SGG) and disialosyl gal-globoside (DSGG), that serve as receptors for uropathogenic E. coli. The overall goal of this proposed project is to understand the basis for host susceptibility to RUTI in young women. The unifying hypothesis we will investigate is that women with recurrent UTls are more often nonsecretors; that nonsecretor status results in increased attachment of uropathogenic E. coli to vaginal and bladder epithelial cells; and that the genetically determined presence of SGG and DSGG on epithelial cells in nonsecretors provides specific receptors for E. coli strains with corresponding adhesins. However, since it is unlikely that inherited factors completely account for increased susceptibility to RUTI in all young women, we will also ascertain the presence or absence of acquired factors thought to predispose to UTI in this patient group and assess their relationship to nonsecretor status and to epithelial cell GSLS. We will accomplish the following specific aims: (1) To evaluate the hypothesis that nonsecretor status is associated with an increased susceptibility to RUTIs in young women, we will conduct a case-control study comparing blood group secretor status in women aged 18 to 30 with RUTI vs. 330 similarly aged control patients without RUTI, adjusting in these analyses for acquired factors that predispose young women to UTI; (2) To evaluate the hypothesis that increased bacterial attachment to uroepithellal cells among women with RUTIs is restricted to nonsecretors, we will collect bladder and vaginal epithelial cells from the patients recruited in Specific Aim I and compare the in vitro attachment of both cloned and wild type P and F fimbriated E. coli strains to epithelial cells from secretors and nonsecretors with a history of RUTI; (3) To evaluate the hypothesis that two specific glycolipids, SGG and DSGG, provide a molecular basis for heightened susceptibility to RUTI in nonsecretors, we will compare bladder epithelial cells collected from secretors and nonsecretors for the presence of surface-exposed SGG and DSGG by utilizing specific monoclonal antibodies to these GSLs in a fluorescence activated cell sorter (FACS) assay; (4) To evaluate the hypothesis that the E. coli strains causing RUTIs in nonsecretors demonstrate specific binding to DSGG and SGG more frequently than strains collected from secretors experiencing RUTIs, we will collect an estimated 315 strains from the patients enrolled in Specific Aim I, characterize them as to P/F fimbriation phenotype, and compare their binding to purified SGG and DSGG. The proposed studies will establish the relative importance of genetic and acquired factors in predisposing young women RUTI and may lead to novel measures for preventing UTI or to the development of specific phenotypic tests to identify high risk individuals. In addition, the detailed knowledge of GSLs on the surface of bladder epithelial cells that will be obtained in this research may well have important implications for other clinical entities such as bacteriuria in elderly women, catheter- associated urinary infections, and interstitial cystitis.
