This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Urinary tract infections (UTIs), most commonly caused by uropathogenic Escherichia coli (UPEC), are associated with substantial morbidity and medical cost. Affected women and children are often plagued with recurrences, and repeated infections of the kidney can lead to renal scarring and chronic kidney disease. Recent work in the murine cystitis model has unveiled new paradigms regarding the pathogenesis of UTI. Long thought to be a strictly extracellular pathogen, UPEC has been shown to invade the epithelial cells lining the bladder and to establish large collections, termed intracellular bacterial communities (IBCs), within these cells. UPEC forms a quiescent reservoir within bladder tissue that resists oral antibiotic therapy and is invisible to host immune defenses, a phenotype that may depend on its unique ability to downregulate host inflammatory cytokine production. This bacterial reservoir can then serve as a seed for recurrent infection, a finding that challenges current dogma that recurrent UTI represents re-inoculation of the urinary tract from a gastrointestinal E. coli population. Current antibiotic regimens are challenged by the development of bacterial resistance and do not eradicate the chronic reservoir. Our recent data demonstrate that a conserved periplasmic chaperone called SurA is critical for the production of adhesive type 1 pili, for the UPEC anti-cytokine phenotype, and for intracellular growth of UPEC during IBC maturation. Disruption of SurA function in UPEC also abolishes formation of the quiescent bacterial reservoir. We will employ tagged SurA proteins in a set of biochemical assays to determine the spectrum of outer membrane substrates of this important conserved chaperone in UPEC. Domain complementation and mutagenesis will be performed to delineate the structural features of, and residues within, SurA that are critical for its support of virulence in UPEC. This knowledge will lead to the development of novel anti-infective compounds that target SurA function and interrupt the IBC pathway and the cycle of recurrent UTI. Relevance: Urinary tract infections represent the second most common infectious disease in the United States, with an annual burden of >7 million outpatient visits and $1 billion in medical cost. Many patients suffer from recurrences that are not only disruptive and painful but can also lead to chronic kidney disease, and current therapies for these patients are insufficient. This proposal identifies a new target for interrupting the cycle of recurrent urinary tract infection.
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