Much of the previous work on the role of bacterial adherence in urinary tract infection has focused on bacterial factors (adhesins) with relatively less attention given to the role of host defense mechanisms. We have recently demonstrated a defective antiadherence activity of bladder extracts (mucin) from patients with recurrent urinary tract infection. Thus in these patients, there may be a functional defect and/or decrease in a factor in the mucin that is responsible for its antibacterial adherence property. A substantial body of animal work indicates that the initial first line defense against invading microorganisms in the urinary tract is the antiadherence activity of the surface mucin layer. Therefore, the structure, chemical composition and physiology of the mucosal surface is such that bacteria are denied attachment to the luminal surface allowing urinary flow to wash them away. A novel approach to the treatment of bladder infection would be the identification and clinical use of agents that either mimic the natural antiadherence activity of the bladder mucosa, augument production of the endogenous mucosal defense factor(s) or break these attachments and thus effectively limit the infection process. The objectives of this proposal are to characterize active antibacterial defense factors of the bladder mucosa and to determine the role these factors play in pathologic states of increased infection susceptibility. To accomplish these goals antibodies are produced to the natural antibacterial defense substance(s) from both bovine and human bladder mucosa. These antibodies are used to develop quantitative and immunohistochemical localization assays in order to determine how these factors come into being and whether they are secreted by an apparenty non-secreting transitional epithelial surface. In addition these antibodies are eventually used to screen expression libraries in order to develop cDNA probes for these factors. The long range goal is to use this insight to develop novel therapies for bladder infection directed at preventing bacterial adherence in patents who are at high risk of developing urinary tract infection. In order to begin develop novel agents it is necessary to first gain an understanding of both the biochemical mechanisms by which bacteria attach to the bladder and the biochemical properties of the natural antibacterial defense factor(s) in bladder muchin.
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