This interdisciplinary SCOR program seeks to understand the epidemiology, pathogenic strategies, and resultant host responses of urinary tract infections (DTI) caused by uropathogenic E. coli (UPEC), one of the most common diseases affecting women. This knowledge will be applied to critically evaluate all aspects of clinical UTI management, including diagnosis, treatment, and prevention. We have proposed an integrative and translational set of experiments that capitalizes on the complementary expertise found in each of the three projects. Basic scientists in Projects 1 and 3 have access to uropathogenic strains collected from women in Project 2 at different clinical stages of UTI. Working together, Projects 1, 2, and 3 will identify genetic and molecular markers and correlates of the different clinical UTI syndromes associated with UPEC infection. These will be pursued both in humans (Project 2) and mice (Project 1) for prognostic indicators of disease outcome: bacterial clearance, asymptomatic infection, chronic colonization, or recurrence. Genotypic and phenotypic profiles of UPEC strains from well-characterized UTI cases will be generated in Project 1 and 3 by blending a powerful genetic system with functional and comparative genomics, defined in vitro and murine models, comparative immunoproteomics, biochemistry, cell biology, laser capture microdissection, antigen discovery techniques, and high resolution electron microscopy. The host response to intracellular bacterial communities (IBCs) and quiescent intracellular reservoirs (QIRs) formed by different UPEC isolates will be examined in detail both in a mouse model (Project 1), using gene and cytokine expression profiling, and in humans (Project 2), by monitoring the adaptive immune response and metabolite profiles in human urine. In addition, exfoliated bladder epithelial cells in mouse and human urine will be screened for evidence of IBC formation, allowing parallel correlation of microscopic assays with clinical outcome in both mice and humans. These efforts promise to connect specific measurements made at the bench to clinical outcomes observed at the bedside. Project 3 will also address primary prevention of UTI by using comparative pan-genomics to study the mechanism by which UPEC emerge from the distal gastrointestinal tract and traverse the perineum to the urethra to cause infection. Completion of these interwoven projects promises to address questions in the clinical management of this ubiquitous disease. ? ? ? ?
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