Gardnerella vaginalis activates host responses necessary for Escherichia coli recurrent UTI from bladder reservoirs

Recurrent urinary tract infections (rUTI) are a costly clinical problem affecting millions of women worldwide each year. The majority of rUTI cases are caused by uropathogenic Escherichia coli (UPEC). Data from humans and mouse models indicate that some instances of rUTI are caused by UPEC emerging from latent reservoirs in the bladder. Some studies have reported that women with vaginal dysbiosis, typically characterized by high levels of Gardnerella vaginalis and other anaerobes, are at increased risk of UTI. Multiple studies have detected G. vaginalis in urine collected by transurethral catheterization (to limit vaginal contamination), suggesting that some women experience routine urinary tract exposures. We recently reported that inoculation of G. vaginalis into the bladder triggers rUTI from UPEC bladder reservoirs in a mouse model. Here we performed whole bladder RNAseq to identify host pathways involved in G. vaginalis-induced rUTI. We identified multiple host pathways differentially expressed following G. vaginalis exposure. At the gene and transcript level, we identified upregulation of the orphan nuclear receptor Nur77 (aka Nr4a1) and Nur77-regulated genes. Pilot data from Nur77 knockout mice suggests that Nur77 is necessary for G. vaganalis exposure to trigger rUTI. A total of 20 mouse bladders, all containing quiescent UPEC reservoirs, were analyzed. 5 bladders from each of the following groups: 12 hours (h) after one PBS exposure (PBS-1), 12h after one G. vaginalis exposure (Gvag-1), 12h after 2 PBS exposures given 12h apart (PBS-2), 12h after 2 G. vaginalis exposures given 12h apart (Gvag-2)