Role of E. coli Virulence Factors in Chronic Prostate Infection and Inflammation

描述(申请人提供)：据估计，在任何时候，各种形式的前列腺炎都会影响9-11%的成年男性，多达16%的男性报告有前列腺炎症状。细菌是急性前列腺炎和一些慢性前列腺炎的主要病原体。急性感染中最常见的分离株是致尿路病原性大肠杆菌菌株。慢性前列腺炎可能由大肠杆菌、克雷伯氏菌、变形杆菌、假单胞菌和肠球菌等细菌引起。慢性前列腺癌感染的后果不仅是患者的发病率，而且由于前列腺组织内产生的长期炎症反应，有可能发展为癌前病变。更清楚地了解导致慢性细菌性前列腺炎的病原体的毒力特性和宿主对感染的反应，对于理解前列腺炎的病理学和癌前病变的病因学至关重要。我们建立了一种经尿路接种致尿路致病性大肠杆菌所致的急、慢性前列腺炎小鼠模型。慢性前列腺癌的组织学特征是前列腺癌的前兆前列腺癌上皮瘤(PIN)的炎性细胞区的渗出。我们认为，小鼠的PIN损伤可能是由炎症诱导的细胞氧化损伤造成的。利用这个小鼠模型和我们在大肠杆菌毒力领域的丰富经验，我们建议定义特定的大肠杆菌毒力因子、急性和慢性感染以及长期感染和炎症引起的病理之间的关系。这项建议的目的是1)确定与急性前列腺癌感染相关的大肠杆菌毒力因子，2)利用这些结果来确定这些毒力因子中哪些对慢性前列腺癌感染是重要的，以及3)阐明大肠杆菌的毒力特性、慢性炎症反应和癌前病变的发展之间的关系。这些研究的结果不仅将确定导致前列腺癌感染的大肠杆菌毒力因素，还将确定那些可能在诱发PIN方面发挥直接或间接作用的因素。这些信息可用于开发感染和PIN开发的新治疗干预措施。慢性前列腺炎在临床上是一个重要的问题，不仅是因为患者的发病率高，而且最近的证据表明，前列腺癌的长期炎症可能在前列腺癌的发生发展中起作用。拟议研究的主要目标是确定与急性和慢性前列腺癌感染相关的大肠杆菌基因。其次，我们将调查哪些大肠杆菌基因在前列腺病变的发生中起直接或间接作用。这些研究的结果可能导致新的方法来预防或治疗慢性细菌性前列腺炎。

DESCRIPTION (provided by applicant): 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.