Investigating the impact of a diabetic urinary environment on group B Streptococcus virulence and host response.

About This Grant

PROJECT SUMMARY/ABSTRACT Group B Streptococcus (GBS) is commonly associated with neonatal infections and can also cause a variety of soft tissue infections, including urinary tract infections (UTI) in non-pregnant adults. However, patients suffering from type 2 diabetes have a significantly higher incidence of GBS UTIs. Additionally, diabetics are more likely to develop complications from UTIs, such as pyelonephritis, urosepsis, and recurrent UTIs. Due to the metabolic/hormonal imbalance that characterizes diabetes, the disease can result in significant urinary tract alterations, including the presence of glucose and fructose in the urine (glycosuria). As metabolism is a significant regulator of both bacterial virulence and host response, I seek to examine glycosuria as a key contributor to the unique susceptibility of diabetic patients to GBS UTI. To discover how the diabetic urinary environment is shaping GBS adaptation, I conducted an RNA-sequencing (RNA-seq) screen on GBS cultured in urine from diabetic, pre- diabetic, and non-diabetic donors under microoxic conditions. The screen identified numerous genes that connect metabolism to virulence regulation. These results are further supported by my preliminary data showing that glycosuria increases GBS survival against reactive oxygen species and neutrophils. Based on these findings, I hypothesize that diabetic glycosuria modulates GBS virulence and host immune responses to promote urogenital colonization and infection. Testing of this hypothesis will be split into two aims: 1) characterize the fitness and virulence impact of candidate GBS genes in the diabetic urinary environment, and 2) evaluate the role of diabetic-associated urinary carbohydrates on immune response to GBS. I will use diabetic urine and healthy urine supplemented with carbohydrates to delineate the broad effects of diabetes from glycosuria on GBS survival against host factors and host epithelial response using complex in vitro urine-tolerant host models. Additionally, I will employ two mouse models, one of type 2 diabetes and one of glycosuria alone, to assess GBS virulence and the host immune response in vivo. This project will provide me with training in mammalian tissue culture and organoid model systems, mouse models of diabetes and UTI, and approaches to assessing host responses to pathogens while also expanding on my background in microbial pathogenesis. Training will take place at Baylor College of Medicine under the mentorship of experts in GBS, UTIs, and the immune response of bladders to infection. Together, this work will provide critical insights into GBS adaptation in diabetic hosts and inform the development of targeted, non-antibiotic interventions for this high-risk population, with potential implications for other pathogens affecting metabolically dysregulated individuals.