Acute uncomplicated urinary tract infections (DTI) occur in an estimated 7-11 million women each year at acumulative cost estimated to exceed $1 billion annually. Approximately 20-30% of women suffer fromfrequent recurrent infections. UTI in young women result in substantial morbidity, time lost from work, andmedical costs. An improved understanding of the pathogenic mechanisms underlying UTI could result innew diagnostics and novel approaches to prevention and treatment resulting in tailored therapies, decreasedantimicrobial use, and decreased morbidity. The goal of this project is to prospectively follow a well definedgroup of patients from acute to recurrent UTI and obtain clinical samples to better understand UTIpathogenesis. The clinical samples will be analyzed throughout this and the accompanying 2 projects tounderstand the ecological niches in which uropathogens reside and persist, the host responses to theprimary acute infection and persistence, and uropathogen virulence repertoires that dictate the interplaybetween pathogen and host resulting in different clinical syndromes such as acute cystitis and asymptomaticbacteruria. In this project, we will prospectively follow a large cohort of women from single isolated acute torecurrent UTI to determine 1) the innate immune response to infection in patients who have a single isolatedUTI vs. those with recurrent infection, differentiating same strain and different strain recurrence andcorrelating elements of the innate response with urovirulence characteristics of the infecting strain, 2) theadaptive response to infection of patients who have a single acute event vs. those with recurrent infectionand 3) the association of intracellular bacterial communities (IBC) and IBC derived factors with recurrent UTI.Through translation from clinical to basic molecular studies, this project will identify unique host responses tosame strain and different strain recurrent UTI. Uropathogenic strains isolated from well-characterizedepisodes of UTI and asymptomatic bacteriuria will be used in Project 1 for comparative genomics to identifyand test the virulence repertoire necessary for different subtypes of UTI. The molecular pathogenesis ofrepresentative strains and the contribution of specific virulence factors to disease will also be examined inProject 1. Uncultured genitourinary tract samples will be evaluated for the evolution of the microbial ecologyfrom acute to recurrent UTI in Project 3. Together these studies will bring together key elements of UTIepidemiology and molecular pathogenesis to develop optimal management and preventative strategies.
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