Genomics of Susceptibility to Urinary Tract Infections

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Recurrent urinary tract infections (RUTI) in adult women are a significant source of patient morbidity and can lead to long-term kidney damage in some cases. Ongoing research by many investigators is directed towards identifying host factors that contribute to increased susceptibility; however, there is not a clear picture of the relative importance of different inherent host factors. A particularly interesting aspect of RUTI susceptibility is the genetic background of affected women because there is a familial predisposition to these infections, and a specific genetic basis to bacterial pyelonephritis has been identified. There are also well-described, genetically determined susceptibilities to severe E. coli bladder and kidney infections in mice, but specific genes that increase bacterial infectivity or impair effective immune responses have not yet been identified. It is clear that innate and adaptive immune responses play major roles in resolving UTIs and preventing upper tract infections; however, the exact nature of these responses, their interdependence, and their genetic basis is not fully understood. Therefore, the overall goal of the proposed research is to use genomic approaches and methods to elucidate the genetics of UTI susceptibility in mice to gain insight into intrinsic host factors and immune functions that are important for resistance to UTIs. The specific aims of this proposal are: 1) to further delineate the genetic basis of susceptibility to induced E. coli bladder and kidney infections through genetic linkage analysis of UTI-susceptible and resistant mice, 2) to breed strains of mice that are congenic for quantitative trait loci shown to be associated with resistance/susceptibility to bladder and kidney infections, and 3) to test the hypothesis that genes associated with resistance to bladder and kidney infections induced by one strain of uropathogenic E. coli confer resistance to similar infections caused by other E. coli strains. These objectives will be accomplished using a well-established mouse model of ascending UTI, genetic linkage analysis, and evaluation of resistance to uropathogens in congenic mice. A better understanding of genetic factors responsible for UTI susceptibility and resistance in mice will make it possible to devise better treatment strategies and potential screening for early detection of susceptible women.