John, P.; Gautam, B.; Kulkarni, R.; Rogers, K. A.

Diabetes mellitus (DM) increases susceptibility to Streptococcus agalactiae (group B Streptococcus or GBS) urinary tract infections (UTI) and exacerbations including pyelonephritis and sepsis, although underlying molecular mechanisms have not been fully deciphered. To address our hypothesis that DM mediated alterations in the host urinary immune defenses increase susceptibility to GBS-UTI, we inoculated, via transurethral route, GBS strain 10/84 into the urinary bladders of 8-weeks old, male/ female, diabetic (denoted as D)/ non-diabetic (ND) mouse littermates. At 24 h post-infection (hpi), compared to their ND littermates, D-mice showed significantly higher GBS CFUs in the bladder, the kidneys, and the spleen. This was accompanied by a significantly reduced recruitment of CD45+ leukocytes to and suppression of pro-inflammatory cytokine production in GBS-infected D-bladder and D-kidneys compared to their ND counterparts. We also noted sex-dependent differences in GBS urinary tissue tropism. For example, D-females exhibited significantly higher bladder burden compared to ND-females, D-males, and ND-males, while the bladder burden in ND-females was not significantly different from that in ND-males. In contrast, ND-males showed significantly higher kidney CFUs than ND-females and DM further increased kidney CFU burden in males. GBS-induced recruitment of CD45+ leukocytes was not different between male and female mice within either D or ND cohorts. GBS-UTI induced significantly higher CXCL1 production in male bladders in both D and ND cohorts compared to their female counterparts. These results indicate that DM increases susceptibility to GBS-UTI and the dissemination to spleen by affecting leukocyte recruitment and pro-inflammatory cytokine production in a sex-dependent manner.