Molecular and genomic basis of the relationship between Gardnerella, bladder exfoliation and E. coli UTI - PROJECT SUMMARY Urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) is a costly clinical problem that affects millions of women worldwide. With a rise in antibiotic resistance among UPEC strains, there is a great need to develop alternative strategies for effective UTI treatment and prevention. This effort relies on understanding what factors modify UTI risk, and how. One of the strongest risk factors for UTI is frequent and/or recent sexual activity. It is likely that vaginal bacteria are commonly introduced to the bladder in sexually active women. Indeed, vaginal genera—most frequently Gardnerella or Lactobacillus—have been frequently isolated from urine collected directly from the bladder. Gardnerella is present at high levels in the vagina in women with the dysbiosis called bacterial vaginosis (BV). Women with BV are at increased risk for UTI and recurrent (r)UTI, but the mechanisms driving this BV-UTI link are unknown. Our new mouse model showed that when Gardnerella gains access to the urinary tract, it triggers apoptosis and exfoliation of the bladder epithelium and enhances UPEC UTI in multiple contexts. Gardnerella increased the level of acute bacteriuria and persistent bladder infection achieved by a subsequent UPEC UTI, and also increased the rate of rUTI by triggering UPEC emergence from quiescent intracellular reservoirs that were formed during a prior infection. Importantly, Gardnerella was rapidly cleared from the host, and was absent by the time UPEC UTI was enhanced. These data and suggest that vaginal bacteria influence UTI outcomes in women in ways that have not yet been appreciated because of the transient nature of their interaction with the bladder – a model we term “covert pathogenesis.” In this proposal we will use our innovative mouse models to specify mechanisms by which Gardnerella enhances UPEC UTI, determine whether this effect extends to other uropathogens (Aim 1), and to utilize genetically diverse Gardnerella strains to define the genetic features of Gardnerella strains that correlate with covert pathogenesis activity in the bladder (Aim 2). Finally, we will specify the association between Gardnerella abundance in the vagina, uroepithelial exfoliation, and rUTI in women, using multiple existing sample banks (Aim 3). This work will fundamentally change the way clinicians and scientists think about, treat, and prevent UTI. Our results could lead to the development of new screening strategies to identify women at risk for rUTI and new approaches to UTI treatment and prevention by targeting vaginal bacteria.
