Beyond the Abstract - Uropathogenic Escherichia coli induces chronic pelvic pain, by Praveen Thumbikat, PhD, et al

BERKELEY, CA ( - Prostatitis is a common urologic disease that results in over 2 million outpatient visits per year in the United States, including 8% of all visits to urologists and 1% of those to primary care physicians.

The disease is classified into four categories, including acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and asymptomatic inflammatory prostatitis. The third disease category, CP/CPPS, accounts for approximately 90% of all chronic prostatitis and is clinically manifested as chronic pain in the perineum, rectum, prostate, penis, testicles and abdomen. Despite the predominantly non-bacterial nature of CP/CPPS, up to 8% of patients with CP/CPPS harbor uropathogens that have traditionally been deemed to be of no significance. CP/CPPS accompanied by uropathogens is differentiated from chronic bacterial prostatitis by the requirement for clinical symptoms of pelvic pain and the lack of recurrent urinary tract infections (UTI).

Several animal models have been developed that induce histological inflammation of the prostate by spontaneous, immune-mediated, and/or infectious methodologies to recapitulate aspects of CP/CPPS. Infection-based models of prostatitis have relied on bacterial strains isolated from the bladder in cystitis or from acute prostatitis. Uropathogenic Escherichia coli UPEC is the most commonly isolated pathogen. While these models reflect key aspects of human acute prostatitis, they may not accurately represent potential pathogens in CP/CPPS and do not address the development of chronic pelvic pain, a distinguishing symptom in CP/CPPS. We therefore hypothesized that infection of the prostate by a UPEC isolate derived from a patient with CP/CPPS would initiate pathogenic processes that establish and sustain chronic pain. In vitro cell culture models and an in vivo murine prostatitis model were used to study the molecular pathogenesis of the CP/CPPS isolate in comparison to a prototypic clinical cystitis isolate.

Molecular and phenotypic characterization of CP1 demonstrated that it lacks a number of the virulence-associated traits that typify acute prostatitis isolates, and UPEC strains generally. The E. coli species is divided into four main phylogenetic groups, commonly designated A, B1, B2, and D. Most E. coli strains responsible for UTIs or other extraintestinal infections belong to group B2 or, less frequently, group D. Our studies place CP1 within group B1, whose members normally lack extra-intestinal virulence factors, but when selected for in clinical disease states can exhibit high levels of virulence. In addition to its phylogenetic background, CP1's virulence gene repertoire also is atypical in comparison to acute prostatitis isolates. This may reflect specific adaptations for chronic prostate colonization that differentiate it from the strains obtained from acute prostatitis.

It has been hypothesized that chronic bacterial prostatitis is characterized by the presence of biofilms. In vitro studies on prostatitis bacteria have demonstrated a greater tendency for the development of biofilm-like structures that are assumed to adhere to the epithelium of the prostate ductal system. Our studies with CP1 suggest that in addition to classical mechanisms of biofilm formation, prostatitis strains possess the ability to invade and persist within the cytoplasm of prostate epithelial cells. The potential to invade and proliferate inside cells would dramatically enhance the ability of these bacteria to resist host immune mechanisms and would provide a unique ecological niche.

We used CP1 to infect two different strains of mice by instillation of bacteria into the urethra using a catheter. Pelvic pain was tested over time in both strains using behavioral measures of pain. Both the NOD and C57BL/6J strains of mice showed equal numbers of bacteria and inflammation after infection but the NOD mice developed chronic pelvic pain while the C57BL/6J mice remained asymptomatic. The NOD mouse is a strain genetically prone to develop different organ-specific autoimmune diseases. Interestingly, the NOD strain of mice can spontaneously develop pelvic pain with advancing age, developing chronic pain by 28 weeks of age. In contrast, 5-7 week old NOD males, infected with CP1, develop pelvic pain that peaks in 3 days and is sustained thereafter. We propose that the CP1 infection of 5-7 week old NOD males initiates and accelerates the known process of autoimmunity in NOD mice, a characteristic that is less likely in C57BL/6J mice. Preliminary studies suggest that differential chemokine and immune responses in the NOD and C57BL/6J mice may mediate the symptomatic variations observed. Interestingly, the differential responses are not simply a function of the host but also a function of the bacterial strain. That is, infection of the NOD male by a different strain of UPEC derived from the bladder is insufficient to activate mechanisms leading to chronic pain, a reminder that host-pathogen interactions are key to mediating the pathogenesis of chronic pelvic pain.

In summary, our study provides experimental evidence for an infectious etiology of chronic pelvic pain. Using a clinical bacterial isolate from a patient with CP/CPPS we recapitulate the symptoms of chronic pain in a murine strain that is predisposed to the development of autoimmunity. Our results implicate characteristics of both the host and the pathogen as key features in determining the development of symptoms. These results have potentially important implications in understanding the pathogenesis of CP/CPPS.



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Praveen Thumbikat, PhD, et al. as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.



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