UREASE--MOLECULAR STUDIES AND ROLE IN PATHOGENESIS

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DESCRIPTION (Adapted from Applicant's Abstract): Urease plays a significant role in bacterial infections of both the urinary tract and the gastroduodenal region. At both sites of infection urease enhances the survival of the infecting organism by providing a more suitable environment for growth. The production of urease also increases damage to the infected organs by direct cellular injury from ammonia. In addition, urinary tract infections with a urea-producing bacteria can result in the formation of bladder and kidney stones. Infection of the urinary tract by urease-producing organisms results in a severe inflammatory response. This proposal examines the urease- specific inflammatory response, since it may lead to renal dysfunction and ultimately glandular scarring or destruction. Our results will be compared to the significant inflammation associated with infection by the urease- producing gastroduodenal pathogen Helicobacter pylori. Understanding the mechanisms of the host response to urease-positive organisms will be important in the development of novel strategies to limit mucosal damage associated with these infections. The two most common urease-producing uropathogens, Providencia stuartii and Proteus mirabilis, express urease in response to urea in the growth medium. Urea-dependent expression requires the regulatory protein UreR, which is a member of the AraC-family of transcriptional activators. In these studies, the UreR-urea interaction and the mechanisms of transcription by UreR will be examined. Urea, which is in high concentrations on human urine, is able to freely diffuse into bacteria, and the UreR-urea interaction is an initial signal to the infecting agent that it is in the urinary tract. Since in urinary tract pathogens UreR is acting as both a sensor of the environment and an activator of transcription, studies on the UreR-urea interaction are important for defining the role of this protein in infection.