Diabetic individuals are more susceptible to urinary tract infections (UTI). Specifically, the risk of UTI caused by
Gram positive Streptococcus agalactiae (Group B Streptococcus, GBS) is significantly increased in diabetic
individuals. In addition, diabetes also facilitates the progression of GBS-UTI to severe and potentially deadly
outcomes such as pyelonephritis, bacteremia, and sepsis. We hypothesize that “the diabetic urinary
microenvironment facilitates infection of the urinary tract 1) by augmenting virulence of uropathogenic
bacteria and 2) by suppressing host immune defenses.” To address this hypothesis, we have proposed
targeted exploratory studies, in alignment with the scope of R21 mechanism, to elucidate GBS factors and host
urinary immune defenses central to GBS-UTI pathogenesis in two mechanistically distinct murine models of
hyperglycemia: 1) STZ-induced type 1 diabetes and 2) db/db, a genetic model of type 2 diabetes.
Previous research has characterized myriad GBS virulence factors such as surface adhesins, pore forming
toxins, and gene regulators facilitating GBS survival and virulence in the urinary tract. Studies using mouse
model of ascending UTI have also revealed distinctive urinary immune responses induced by GBS-UTI.
However, two important knowledge gaps exist in our understanding of GBS-UTI pathogenesis in diabetes:
1) the pleiotropic effects of host diabetic urinary microenvironment on GBS physiology are undefined and
2) specific host mechanisms responsible for increased urinary GBS burden observed in diabetic mice are not
fully deciphered. To fill these knowledge gaps we propose:
Specific Aim 1 Identify and characterize specific GBS factors important for uropathogenesis in diabetic
mice. We will compare RNA-sequencing profiles of GBS isolated from diabetic and non-diabetic urinary tracts
to identify differentially transcribed virulence, regulatory and metabolic gene expression networks. The
experiments proposed in SA1 are founded on our published results that in vitro exposure to moderate
glycosuria significantly increases GBS virulence.
Specific Aim 2 Evaluate pathophysiology of GBS-UTI in type 1 and type 2 diabetic mice. In this aim we
will induce ascending UTI by inoculating GBS into STZ-type 1 and db/db type 2 diabetic mice and their non-
diabetic littermates and examine differences in disease parameters such as bacterial burden, cytokine
production, immune cell infiltration and histopathology of the urinary tract. The experiments in SA2 are founded
on supporting data that at 24h after intravesicular inoculation with GBS, db/db diabetic mice exhibit significantly
higher bacterial burden in bladder and kidneys and increased dissemination to spleen.
In addition to heralding significant advances in the field of GBS-UTI, our results will pave the way for research
into the effects of diabetes on the pathogenesis of other uropathogens, identifying novel host/pathogen targets
against which small molecular inhibitors may ultimately be developed as effective therapeutics to treat UTI.