Estimates are that the various forms of prostatitis affect 9-11% of adult men at any one time, and up to 16% of men have reported having prostatitis symptoms. Bacteria are the primary etiological agents in acute prostatitis and in a some chronic prostatitis cases. The most common isolates in acute infections are uropathogenic E. coli strains. Chronic prostatitis may caused by E. coli, and bacteria such as Klebsiella, Proteus, Pseudomonas, and Enterococcus species. The consequences of chronic prostate infections are not only patient morbidity but the potential for development of preneoplastic lesions due to long-term inflammatory responses generated within prostate tissue. Developing a clearer picture of the virulence properties of pathogens responsible for chronic bacterial prostatitis and host responses to infection are critical to understanding the pathology of prostatitis and etiology of preneoplastic lesions. We have developed a mouse model of acute and chronic prostatitis induced by intraurethral inoculation with uropathogenic E. coli. Histologic features of chronically infected prostates are infiltration of inflammatory cells areas of prostatic epithelial neoplasia (PIN), believed to be a precursor to prostate cancer. We believe that PIN lesions in mice may have resulted from inflammation-induced cellular oxidative damage. Using this mouse model and our extensive experience in the field of E. coli virulence we propose to define relationships between specific E. coli virulence factors, acute and chronic infections, and the pathology induced by long-term infection and inflammation. The objectives of this proposal are to 1) define E. coli virulence factors associated with acute prostate infection, 2) utilize these results to define which of those virulence factors are important for chronic prostate infections, and 3) elucidate the relationships between virulence properties of E. coli, chronic inflammatory responses, and development of preneoplastic lesions. Results from these studies will not only identify those E. coli virulence factors contributing to prostate infection but also those that may play a direct or indirect role in inducing PIN. This information can be used to develop novel treatment interventions for infection and PIN development. Chronic prostatitis in an important clinical problem not only because of patient morbidity but also recent evidence that long-term prostatic inflammation may play a role in development of prostate cancer. The primary objective of the proposed studies is to define E. coli genes associated with acute and chronic prostate infection. Secondarily, we will investigate which E. coli genes play a direct or indirect role in development of prostatic lesions. Results of these studies can lead to new methods to prevent or treat chronic bacterial prostatitis. ? ? ?