P. mirabilis is not a common cause of UTI in the normal host but does infect a high proportion of patients with complicated urinary tracts, i.e., those with functional or anatomic abnormalities or with chronic instrumentation such as long-term catheterization. In these patients, not only does this bacterium cause cystitis and acute pyelonephritis, but the production of urinary stones, a hallmark of infection with this organism, add another dimension to the already complicated urinary tract. Stone formation is caused by the expression of a highly active urease which hydrolyzes urea to ammonia, causing local pH to rise with subsequent precipitation of magnesium ammonium phosphate (struvite) and calcium phosphate (apatite) crystals. In addition to urease, we have also identified MR/P (mannose-resistant/Proteus-like) fimbriae, PMF (P. mirabilis fimbriae), and flagella as virulence factors that are essential for colonization of the urinary tract. Because we are beginning to understand the molecular mechanisms by which P. mirabilis establishes infection, evades the host defense, and damages host tissue, and because we can identify a large and well defined group of patients who are affected by this species, and because there is evidence that vaccination would prevent infections, we propose, as Specific Aims for the current proposal, 1) To identify and characterize new virulence and regulatory determinants of uropathogenic Proteus mirabilis; 2) To localize bacteria in relation to specific cell types during experimental UT1 and assess expression of virulence factors in different locations and phases of infection (e.g., PMF in bladder, flagella in ureter, MR/P in kidney); and 3) To investigate MR/P fimbrial adhesion structure and function and develop an adhesin- based vaccine to protect against Proteus UT1 and uroliathiasis. To accomplish these aims, signature tagged mutagenesis. To accomplish these aims, signature tagged mutagenesis and other molecular techniques, confocal laser scanning microscopy, and the CBA mouse model of ascending UT1 will be used.
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