Impact of Host Age and Parity on Susceptibility to Severe Urinary Tract Infection in a Murine Model

Abstract

The epidemiology and bacteriology of urinary tract infection (UTI) varies across the human lifespan, but the reasons for these differences are poorly understood. Using established monomicrobial and polymicrobial murine UTI models caused by uropathogenic Escherichia coli (UPEC) and/or Group B Streptococcus (GBS), we demonstrate age and parity as inter-related factors contributing to UTI susceptibility. Young nulliparous animals exhibited 10–100-fold higher bacterial titers compared to older animals. In contrast, multiparity was associated with more severe acute cystitis in older animals compared to age-matched nulliparous controls, particularly in the context of polymicrobial infection where UPEC titers were ∼1000-fold higher in the multiparous compared to the nulliparous host. Multiparity was also associated with significantly increased risk of chronic high titer UPEC cystitis and ascending pyelonephritis. Further evidence is provided that the increased UPEC load in multiparous animals required TLR4-signaling. Together, these data strongly suggest that the experience of childbearing fundamentally and permanently changes the urinary tract and its response to pathogens in a manner that increases susceptibility to severe UTI. Moreover, this murine model provides a system for dissecting these and other lifespan-associated risk factors contributing to severe UTI in at-risk groups.

Increased Age, but Not Parity Predisposes to Higher Bacteriuria Burdens Due to Streptococcus Urinary Tract Infection and Influences Bladder Cytokine Responses, Which Develop Independent of Tissue Bacterial Loads

“…agalactiae UTI [24] reported lower bladder colonisation in aged mice vs. young mice, and higher colonisation with parity [24]. The results of the current study show (i) equivalent levels of bladder tissue colonisation in young and aged mice, in contrast to prior findings [24], (ii) equivalent levels of bladder tissue colonisation in young and dam mice, consistent with [24], (iii) increased age, but not parity predisposes to higher bacteriuria burdens during S . agalactiae UTI, and (iv) both age and parity effect the patterns of production of several regulatory and pro-inflammatory cytokines, including KC, MCP-1, IL-17, MIP-1α and RANTES that are expressed during S .…”

“…Bacteriuria is a central aspect of UTI and can be important in the context of ABU and persistent colonization of urine [15, 30, 31]; bacteriuria was not studied in a prior report of S . agalactiae UTI in aged mice [24]. In a clinical context, studies have shown higher prevalence rates of bacteriuria in elderly populations, as reviewed elsewhere [18].…”

“…S . agalactiae bladder colonisation in mice, reported in [24], was also found to be higher in young mice (8–10 weeks) compared to aged mice (7–11 months) [24], implying that younger age may predispose to S . agalactiae UTI; however, the study did not analyse cytokine responses nor assess levels of bacteriuria in the model.…”

“…In this context, one recent study examined age and parity in S . agalactiae UTI and reported that parity increases bacterial colonisation of the bladder in multiparous mice compared to nulliparous mice [24]. S .…”

“…agalactiae UTI using murine models incorporating distinct groups of mice to model states of young and old age, and nulliparous vs. multiparous backgrounds. We examined infection in the bladder, as reported previously [24], and bacteriuria and inflammatory mediators in the bladder that might influence UTI, but which have not been examined previously.…”