Recurrent urinary tract infections (RUTI) in adult women are a significant source ofpatient morbidity and can lead to long-term kidney damage in some cases. Ongoingresearch by many investigators is directed towards identifying host factors thatcontribute to increased susceptibility; however, there is not a clear picture of the relativeimportance of different inherent host factors. A particularly interesting aspect of RUTIsusceptibility is the genetic background of affected women because there is a familialpredisposition to these infections, and a specific genetic basis to bacterial pyelonephritishas been identified. There are also well-described, genetically determinedsusceptibilities to severe E. coli bladder and kidney infections in mice, but specific genesthat increase bacterial infectivity or impair effective immune responses have not yetbeen identified. It is clear that innate and adaptive immune responses play major rolesin resolving UTIs and preventing upper tract infections; however, the exact nature ofthese responses, their interdependence, and their genetic basis is not fully understood.Therefore, the overall goal of the proposed research is to use genomic approaches andmethods to elucidate the genetics of UTI susceptibility in mice to gain insight intointrinsic 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 ofsusceptibility to induced E. coli bladder and kidney infections through genetic linkageanalysis of UTI-susceptible and resistant mice, 2) to breed strains of mice that arecongenic for quantitative trait loci shown to be associated with resistance/susceptibility tobladder and kidney infections, and 3) to test the hypothesis that genes associated withresistance to bladder and kidney infections induced by one strain of uropathogenicE. coli confer resistance to similar infections caused by other E. coli strains. Theseobjectives 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 andresistance in mice will make it possible to devise better treatment strategies andpotential screening for early detection of susceptible women.
| Suhs, Kaleigh A; Marthaler, Brodie R; Welch, Rodney A et al. (2011) Lack of association between the Tlr4 (Lpsd/Lpsd) genotype and increased susceptibility to Escherichia coli bladder infections in female C3H/HeJ mice. MBio 2:e00094-11 |
| Hopkins, Walter J; Elkahwaji, Johny; Kendziorski, Christina et al. (2009) Quantitative trait loci associated with susceptibility to bladder and kidney infections induced by Escherichia coli in female C3H/HeJ mice. J Infect Dis 199:355-61 |
