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 Lps(d) and Lps(n) alleles with bladder infection susceptibility by using genetic crosses of C3H/HeJ mice with Tlr4 (Lps(n)/Lps(n)) or (Lps(n)/Lps(d)) mice. Heterozygous offspring of C3H/HeJ (Lps(d)/Lps(d)) × BALB/cAnN (Lps(n)/Lps(n)) mice successfully resolved bladder infections induced by a uropathogenic E. coli strain, while heterozygous mice from a C3H/HeJ (Lps(d)/Lps(d)) × C3H/HeOuJ (Lps(n)/Lps(n)) cross had severe infections. A backcross of C3H/HeJ (Lps(d)/Lps(d)) with (BALB/cAnN × C3H/HeJ)F(1) (Lps(n)/Lps(d)) produced mice that were either resistant or susceptible to E. coli bladder infections and had Lps(d)/Lps(d) or Lps(n)/Lps(d) Tlr4 genotypes. The Lps(d)/Lps(d) or Lps(n)/Lps(d) genotypes were present in individual mice with unresolved bladder infections, and the Lps(d)/Lps(d) 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.
Importance: We have previously demonstrated that mouse strains with either a functional or nonfunctional Tlr4 were not able to resolve induced Escherichia coli bladder infections and that a chromosomal site distinct from Tlr4 was associated with an inability to resolve bladder infections in C3H/HeJ mice. The present study has further investigated the relevance of Tlr4 in bladder infection resolution by defining the Tlr4 alleles present in offspring of genetic crosses of C3H/HeJ mice with infection-resistant and -susceptible inbred strains. The results of these experiments showed that mice with a normal Tlr4 on different genetic backgrounds were not able to clear E. coli bladder infections and that animals with a defective Tlr4 could successfully resolve infections. These results strongly imply the presence of a gene other than in Tlr4 as an important genetic determinant of infection resistance/susceptibility in C3H/HeJ and other inbred mouse strains used in mouse models of infectious diseases.