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

Abstract

Streptococcus agalactiae causes urinary tract infection (UTI) in pregnant adults, non-pregnant adults, immune-compromised individuals and the elderly. The pathogenesis of S. agalactiae UTI in distinct patient populations is poorly understood. In this study, we used murine models of UTI incorporating young mice, aged and dam mice to show that uropathogenic S. agalactiae causes bacteriuria at significantly higher levels in aged mice compared to young mice and this occurs coincident with equivalent levels of bladder tissue colonisation at 24 h post-infection (p.i.). In addition, aged mice exhibited significantly higher bacteriuria burdens at 48 h compared to young mice, confirming a divergent pattern of bacterial colonization in the urinary tract of aged and young mice. Multiparous mice, in contrast, exhibited significantly lower urinary titres of S. agalactiae compared to age-matched nulliparous mice suggesting that parity enhances the ability of the host to control S. agalactiae bacteriuria. Additionally, we show that both age and parity alter the expression levels of several key regulatory and pro-inflammatory cytokines, which are known to be important the immune response to UTI, including Interleukin (IL)-1β, IL-12(p40), and Monocyte Chemoattractant Protein-1 (MCP-1). Finally, we demonstrate that other cytokines, including IL-17 are induced significantly in the S. agalactiae-infected bladder regardless of age and parity status. Collectively, these findings show that the host environment plays an important role in influencing the severity of S. agalactiae UTI; infection dynamics, particularly in the context of bacteriuria, depend on age and parity, which also affect the nature of innate immune responses to infection.

Urine Cytokine and Chemokine Levels Predict Urinary Tract Infection Severity Independent of Uropathogen, Urine Bacterial Burden, Host Genetics, and Host Age

“…Thus, age-dependent differences in the innate immune response to infection could lead to differences in uropathogen colonization susceptibility. This was recently demonstrated for experimental S. agalactiae infection, in which aged mice exhibited increased IL-1␣, IL-12 (p40), granulocyte colony-stimulating factor (G-CSF), and CCL5 (RANTES) and decreased IL-3, IL-4, IL-9, and IL-10 compared to levels in young mice (31).…”

“…Similarly, inoculation of young C57BL/6 mice with S. agalactiae induces IL-1␣, IL-1␤, IL-6, CCL5 (RANTES), and CXCL5 (LIX), but not TNF-␣ (34), while infection with E. coli induces IL-10, IL-17, IL-23, TNF-␣, and CXCL1 (KC) in addition to IL-1␣, IL-1␤, IL-6, CCL5 (RANTES), and CXCL5 (LIX) (28,35). It is also notable that parity (multiple gestations) influences S. agalactiae and E. coli colonization susceptibility, and this is at least partly mediated through Toll-like receptor 4 (TLR4)-stimulated inflammation (31,36). Host genetics also appear to influence age-dependent differences in uropathogen susceptibility as differences in colonization and disease severity have been observed between mouse strains (31,36).…”

“…It is also notable that parity (multiple gestations) influences S. agalactiae and E. coli colonization susceptibility, and this is at least partly mediated through Toll-like receptor 4 (TLR4)-stimulated inflammation (31,36). Host genetics also appear to influence age-dependent differences in uropathogen susceptibility as differences in colonization and disease severity have been observed between mouse strains (31,36).…”

Determination of surface proteins profile, capsular genotyping, and antibiotic susceptibility patterns of Group B Streptococcus isolated from urinary tract infection of Iranian patients

“…Streptococcus agalactiae , also known as Group B streptococcus (GBS), is a common commensal of the human gastrointestinal and genitourinary tracts [1]. In addition to causing a broad range of infectious diseases in neonates, pregnant women, the elderly and the immunocompromised, this organism is responsible for approximately 2–3% of all urinary tract infections (UTI) [2–4]. Diabetes mellitus, immunocompromised individuals and chronic renal failure may be risk factors for GBS UTI [5, 6].…”

Bladder urothelial BK channel activity is a critical mediator for innate immune response in urinary tract infection pathogenesis

“…However, IL-1␤ was not increased by either LPS or UPEC after 2 h in this study. Other investi-gators using urothelial cancer cell cultures failed to detect increased IL-1␤ (6,20). There was increased urinary IL-1␤ in only young female mice in response to Streptococcus agalactiae 24 h after bacterial exposure, which dissipated after 48 h (20).…”