Uropathogenic Escherichia coli invade luminal prostate cells via FimH–PPAP receptor binding

Bacterial prostatitis caused by uropathogenic Escherichia coli (UPEC) strains is a highly prevalent and recurrent infection responsible for significant morbidity in men. The molecular pathogenesis of prostatitis remains poorly understood, partly due to a lack of suitable in vitro models. Here we developed a 2D mouse stem cell-derived prostate epithelial organoid model. In the organoid model, 5α-dihydrotestosterone promoted differentiation of basal into luminal cells, while transcriptomic analyses validated the model in comparison to 3D models and mouse prostate tissue. Infection analyses revealed that UPEC preferentially attached to, invaded and replicated within luminal prostate cells. Experiments with a UPEC mutant strain lacking the bacterial adhesin, FimH, alongside immunoprecipitation, mass spectrometry, biochemistry and infection experiments with host gene knockouts revealed that FimH-prostatic acid phosphatase (PPAP) binding interactions promote UPEC invasion of luminal prostate cells. ᴅ-Mannose competitively inhibited FimH-PPAP interactions. Findings were validated using ex vivo human prostate tissue. These data highlight the adaptability of FimH in engaging host receptors and the potential for FimH-targeting strategies to reduce bacterial prostatitis.