Genomics of Susceptibility to Urinary Tract Infections

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DESCRIPTION (provided by applicant): 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 is directed towards identifying host factors that contribute to increased susceptibility; however, as yet there is not a clear picture of the relative importance of different inherent host factors. A better understanding of the genetic basis of intrinsic host factors it will make it possible to devise new therapies that overcome genetic deficiencies and to develop screening methods for early detection of susceptible individuals. There is very likely a strong familial predisposition to RUTIs, and a genetically determined susceptibility to severe bladder and kidney infections has been demonstrated in mice. Specific genes that increase bacterial infectivity or impair effective immune responses have not yet been identified in mice or humans. 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 and to delineate intrinsic host factors and immune functions that are important for host resistance to UTIs. The specific aims of this proposal are: 1) to test the hypothesis that specific genetic loci in mice are associated with increased susceptibility or resistance to induced E. coil bladder and kidney infections by genetic linkage analysis of UTI-resistant and susceptible mice using DNA microsatellite chromosomal markers and selectively breed strains of mice that are congenic for these resistance genes and 2) to test the hypothesis that genes associated with resistance to bladder and kidney infections induced by one strain of uropathogenic E. coil confer resistance to similar infections caused by other E. coli strains or non-E, coil bacteria. 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.