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Background: The C3H/HeJ mouse strain develops severe bladder and kidney infections after receiving intravesical inoculation with uropathogenic Escherichia coli. This susceptibility is genetically determined, but the specific genes involved have not been completely defined. The objective of the present study was to use quantitative trait locus (QTL) mapping to identify chromosomal sites associated with susceptibility to infection in C3H/HeJ mice., Methods: Female mice from a backcross of C3H/HeJ and (BALB/cxC3H/HeJ)F1 mice were inoculated with E. coli, and the number of E. coli colony-forming units present in the bladder and kidneys was quantified 10 days later. Genomic DNA was scanned using microsatellite markers to localize chromosomal segments derived from parental strains. Statistical analyses associated infection phenotypes with chromosomal sites., Results: A highly significant QTL for susceptibility to bladder infection was identified on chromosome 4, and C3H/HeJ alleles at this locus interacted with BALB/c alleles on chromosome 19 to increase the severity of infection. A significant QTL on chromosome 6 was associated with severe kidney infections., Conclusions: Increased susceptibility to E. coli bladder and kidney infections in female C3H/HeJ mice is associated with specific chromosomal sites located near genes contributing to host resistance to infection. The results demonstrate the multigenic nature of susceptibility to urinary tract infections.