Time course and host responses to Escherichia coli urinary tract infection in genetically distinct mouse strains

Abstract

Recurrent urinary tract infections (UTIs) are a significant clinical problem for many women; however, host susceptibility factors have not been completely defined. The mouse model of induced UTI provides an experimental environment in which to identify specific host characteristics that are important in initial bacterial colonization of the urinary tract and in resolution of an infection. This study examined initial susceptibility, bacterial clearance, and host defense mechanisms during induction and resolution of Escherichia coli UTIs in genetically distinct strains of mice. Of the ten inbred strains tested, six (BALB/c, C3H/HeN, C57BL/6, DBA.1, DBA.2, and AKR) showed progressive resolution of bladder infections over a 14-day period. A constant, low-level bladder infection was observed in SWR and SJL mice. High bladder infection levels persisted over the 14-day study period in C3H/HeJ and C3H/OuJ mice. Kidney infection levels generally correlated with bladder infection levels, especially in C3H/HeJ and C3H/OuJ mice, the two most susceptible strains, in which infections became more severe with time after challenge. The degree of inflammation in bladder and kidneys, as well as antibody-forming cell responses, positively correlated with infection intensity in all strains except C3H/HeJ, which had minimal inflammation despite high infection levels. These results demonstrate two important aspects of host defense against UTI. First, the innate immune response to an infection in the bladder or kidneys consists primarily of local inflammation, which is followed by an adaptive response characterized in part by an antibody response to the infecting bacteria. Second, a UTI will be spontaneously resolved in most cases; however, in mice with specific genetic backgrounds, a UTI can persist for an extended length of time. The latter result strongly suggests that the presence or absence of specific host genes will determine how effectively an E. coli UTI will be resolved.

FIG. 1

Time course of E. coli bladder infections in inbred mouse strains. Mice were inoculated intravesically with 10⁸ E. coli CFU on day 0 and sacrificed at day 1, 3, 7, or 14. Each point represents the mean number of E. coli CFU in bladders from 5 or 6 mice. ○, AKR; ⊡, BALB/c; •, C3H/HeJ; ◊, C3H/HeN; ▪, C3H/OuJ; □, C57BL/6; ▴, DBA.1; ▵, DBA.2; ×, SJL; +, SWR.

FIG. 2

Time course of E. coli kidney infections in inbred mouse strains. Mice were inoculated intravesically with 10⁸ E. coli CFU on day 0 and sacrificed at day 1, 3, 7, or 14. Each point represents the mean number of E. coli CFU in kidneys from 5 or 6 mice. Symbols are as defined for Fig. 1.

FIG. 3

Bladder inflammation scores for inbred mouse strains during the course of E. coli UTIs. Mice were inoculated intravesically with 10⁸ E. coli CFU on day 0 and sacrificed at day 1, 3, 7, or 14. The degree of inflammation over the total area of each section was graded according to the criteria in Table 1. Each point represents the mean inflammation score of 5 or 6 mice. Symbols are as defined for Fig. 1.

FIG. 4

Kidney inflammation scores for inbred mouse strains during the course of E. coli UTIs. Mice were inoculated intravesically with 10⁸ E. coli CFU on day 0 and sacrificed at day 1, 3, 7, or 14. The degree of inflammation over the total area of each section was graded according to the criteria in Table 1. Each point represents the mean inflammation score of 5 or 6 mice. Symbols are as defined for Fig. 1.

FIG. 5

Anti-E. coli splenic AFC responses in inbred mouse strains during the course of E. coli UTIs. Mice were inoculated intravesically with 10⁸ E. coli CFU on day 0 and sacrificed at day 1, 3, 7, or 14. AFCs in the spleen were detected by an enzyme-linked immunosorbent spot assay using whole E. coli cells as the target antigens. Each point represents the mean inflammation score of 5 or 6 mice. Symbols are as defined for Fig. 1.