PROSTUPEC

Millions of men suffer from bacterial prostatitis caused by uropathogenic E. coli (UPEC). Similar to bladder infection, acute prostatitis can lead to chronicity and long-term morbidity, including urinary and sexual dysfunction. Despite these grave consequences, UPEC pathogenesis and chronic prostatitis remain poorly understood. In PROSTUPEC, we will decipher the molecular mechanisms by which UPEC establishes acute and chronic prostatitis. Based on our preliminary and published data, we hypothesize that specific host factors in the prostate, distinct from those in the bladder, influence UPEC infection. We will test whether factors, including membrane receptors, intracellular signaling, and immune responses, contribute to the initiation, progression, or chronicity of prostatitis. To test our hypothesis, we will: 1) Delineate the early dynamics of UPEC infection in the prostate, compared to the bladder, using our established mouse infection models and mouse organoids; 2) Investigate how local interactions among epithelial and immune cells and UPEC impact infection outcomes, using spatial transcriptomics and the MACSima Imaging System in mice and a newly developed human organoid model; and 3) Evaluate whether host factors identified can serve as targets for anti-infective therapies. As a proof of concept, we will begin by blocking the prostate receptor PPAP, a novel receptor we recently discovered as a pathway for UPEC invasion into prostate cells. To ensure success, each Aim will be executed in close collaboration, with the Ingersoll lab focusing on mouse models and immune response analyses, including MACSima spatial imaging; and the Aguilar lab specializing in mouse and human organoid models, RNA-sequencing, and imaging analysis. Together, this work will uncover key host factors that regulate prostate infection in physiologically relevant models of prostate tissue, enhancing the potential translational impact of the findings.