Urinary tract infections (UTIs) are common infections that affect a large proportion of the world population and account for significant morbidity and medical expenditures. These infections are most commonly caused by Escherichia coli (E. coli). A long-term goal of this proposal is to understand the processes by which E. coli causes acute, recurrent and chronic UTIs and the sequelae of these infections. An integrated approach will be used that blends a powerful bacterial genetic system, a mouse UTI model, and x-ray crystallography with high-resolution electron microscopy (EM), protein chemistry, carbohydrate chemistry, and tissue culture systems in order to reveal the cellular, molecular, and structural basis for the pathogenesis of these infections. The FimH adhesin present at the tip of type 1 pili has been shown in animal models to mediate binding to the uroplakin-coated lumenal surface of the bladder. The uroplakin receptor complexes recognized by the FimH adhesin will be cloned and used to investigate the consequences of FimH-uroplakin interactions. Also, the three dimensional structure of the FimH adhesin will be used to design a panel of site directed mutations to delineate the mannose binding pocket of the FimH adhesin and the structural basis of bacterial colonization of the urinary tract. The adaptive responses to bladder infections and the activation of signals that lead to the release of cytokines and recruitment of neutrophils will be dissected in detail. FimH-mediated attachment to the bladder epithelial cells activates a cascade of innate defenses that leads to rapid exfoliation and proliferation of underlying epithelial cells. The molecular basis of exfoliation will be investigated and its role in protecting the bladder from infection will be studied. The molecular mechanisms by which uropathogenic E. coli are able to invade bladder epithelial cells and evade the host response will be elucidated. Uropathogenic E. coli replicate intracellularly and form """"""""bacterial factories"""""""" in the lumenal superficial facet cells of the bladder. The virulence factors required for this process will be identified and studied. Finally, the fluxing of E. coli out of the facet cells and colonization of underlying tissue will be investigated as a mechanism to cause persistent and recurrent infections. These studies will contribute to the development of adhesin-based vaccines to treat and prevent urinary tract infections and their sequelae.
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