URINARY TRACT INFECTIONS--IMMUNE BASIS OF SUSCEPTIBILITY

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DESCRIPTION (Adapted from the Applicant's Abstract): Urinary tract infections (UTI) are estimated to occur in up to 50% of all women in their lifetimes. Approximately seven million women per year develop acute infections that account for an estimated one billion dollars in health care costs. Recurrent infections develop in 10-15% of adult women and require ongoing medical care and use of antibiotics both acutely and prophylactically. In addition, lower tract infections can ascend to the kidneys, possibly leading to kidney damage or bacteremia. Host resistance to UTI's is comprised of several different mechanisms that include innate immunity, inflammatory responses, and adaptive immune responses. Cytokines, phagocytes, natural killer cells, and T cells are active in host defense to infections. Our preliminary results have shown that functional deficiencies in any of these components leads to increased severity of infections in the bladder and kidneys of experimental animals. There is also evidence that innate and early cellular defenses can act to prevent bladder infections from ascending to the kidneys. Preliminary genetic studies have indicated that increased host susceptibility to UTI's has a heritable component. Therefore, the overall objective is to more clearly define the host responses that are active during a UTI and to identify genetic factors that increase susceptibility. The specific aims are: 1) to identify the role of cellular host defense mechanisms that are active during a UTI and, in particular those that are most important in preventing lower tract infections from ascending to the kidneys; 2) to evaluate the hypothesis that antibody-mediated hyporesponsiveness to E. coli antigens in UTI-susceptible women is associated with T cell regulation or induction of antibody responses; 3) to evaluate the hypothesis that a heritable trait increases the susceptibility to some women to recurrent UTIs by analysis of familial inheritance patterns; 4) to evaluate the hypothesis that a genetic locus (or loci) in mice will increase susceptibilityto an induced UTI.