Diabetes Mellitus Affects Urinary Tissue Tropism of Group B Streptococci in a Sex-Dependent Manner

Diabetes mellitus (DM) increases the risk of Streptococcus agalactiae (group B Streptococcus; GBS) urinary tract infections (UTIs) and severe complications, including pyelonephritis and bacteremia, although underlying molecular mechanisms are unclear. We hypothesized that DM-associated alterations in urinary tract immunity drive GBS-UTI susceptibility. To address this hypothesis, we examined GBS-UTI pathogenesis in db/db obese hyperglycemic mice. At 24 h post-infection, diabetic (D-) mice showed significantly higher GBS burden in the bladder and the spleen compared to non-diabetic (ND-) controls. This was accompanied by significant dysregulation of the local innate immune response, including reduced leukocyte recruitment and blunted pro-inflammatory cytokine production in both the bladder and kidneys. We also identified sex differences in GBS tissue tropism. D-females showed a higher bladder burden than ND-females, ND-males, and D-males. In contrast, significantly higher kidney burden in ND-males than ND-females was further exacerbated by DM. This correlated with pronounced differences in CXCL-1 levels between male and female bladders in both D and ND cohorts, although sex did not affect immune cell recruitment. Together, these results suggest an association between obese hyperglycemia-mediated increased susceptibility to GBS-UTI and systemic dissemination and impaired local immune responses. In addition, our results also reveal sex-dependent differences in GBS urinary tract colonization.