Background
The C3H/HeJ strain of mice develop severe bladder and kidney infections after intravesical inoculation with uropathogenic E. coli. This susceptibility is genetically determined, but the specific genes involved have not been completely defined. The objective of the current study was to use quantitative trait locus (QTL) mapping to identify chromosomal sites in C3H/HeJ mice associated with infection susceptibility.
Methods
Female mice from a backcross of C3H/HeJ and (BALB/c × C3H/HeJ)F1 mice were inoculated with E. coli, and the number of E. coli present in the bladder and kidneys was quantified ten 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 bladder infection susceptibility was identified on chromosome 4, and C3H/HeJ alleles at this locus interacted with BALB/c alleles on chromosome 19 to increase infection severity. 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 UTI susceptibility.
Toll-like receptor 4 is thought to have a primary role in host defense against Escherichia coli bladder colonization, based on mouse models of urinary tract infection using C3H/HeJ female mice. This strain carries a point mutation in the Tlr4 gene, which renders the mice unresponsive to lipopolysaccharide (LPS) and thus limits the bladder inflammatory response and infection resolution. The importance of Tlr4 as the sole genetic determinant of resistance or susceptibility can be questioned, however, by the observation that C3H/HeOuJ female mice with a functional Tlr4 do not effectively resolve E. coli bladder infections. The present study further examined this inconsistency by investigating the association of Tlr4 Lpsd and Lpsn alleles with bladder infection susceptibility by using genetic crosses of C3H/HeJ mice with Tlr4 (Lpsn/Lpsn) or (Lpsn/Lpsd) mice. Heterozygous offspring of C3H/HeJ (Lpsd/Lpsd) × BALB/cAnN (Lpsn/Lpsn) mice successfully resolved bladder infections induced by a uropathogenic E. coli strain, while heterozygous mice from a C3H/HeJ (Lpsd/Lpsd) × C3H/HeOuJ (Lpsn/Lpsn) cross had severe infections. A backcross of C3H/HeJ (Lpsd/Lpsd) with (BALB/cAnN × C3H/HeJ)F1 (Lpsn/Lpsd) produced mice that were either resistant or susceptible to E. coli bladder infections and had Lpsd/Lpsd or Lpsn/Lpsd Tlr4 genotypes. The Lpsd/Lpsd or Lpsn/Lpsd genotypes were present in individual mice with unresolved bladder infections, and the Lpsd/Lpsd genotype was found in infection-resistant mice. These results indicate that at least one gene other than Tlr4 strongly influences susceptibility to E. coli bladder infections in C3H/HeJ mice.
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