While Proteus mirabilis is not a common cause of UTI in the normal host, P. mirabilis causes a high incidence of infection in patients with complicated urinary tracts, i.e., those with functional or anatomic abnormalities or with chronic instrumentation. P. mirabilis expresses a number of proteins, including urease, hemolysin, flagella, fimbriae (four distinct types: MR/P, PMF, ATF, and NAF), amino acid deaminase, and IgA protease, that have been postulated to be virulence factors in urinary tract infection. In our experimental approach, we have identified proteins encoded by the virulence genes, isolated the corresponding gene sequences, constructed specific mutations within these sequences in vitro, introduced these mutations back into the wild type parental strain by allelic exchange, and assessed the contribution to virulence of each specific protein in a mouse model of ascending urinary tact infection. In the current application, we propose to continue our investigation by assessing factors proven to contribute to colonization as well as to analyze newly discovered factors that may play a role in infection. We will then apply these findings towards the development of a vaccine for the prevention of Proteus urinary tract infection.
As specific aims, we propose to: 1. Identify the MR/P fimbrial adhesion that binds to a receptor on kidney epithelial cells; 2. measure in vivo levels of expression of urease, hemolysin, flagella, fimbriae, deaminase, and protease genes during experimental infection; 3. determine the contribution to virulence in a mouse model of ascending UTI of : a. ATF fimbriae, b. NAF fimbriae, c. Amino acid, deaminase, d. IgA protease; 4. determine whether P. mirabilis avoids host defense by flagellar antigenic variation; and 5. initiate development of a vaccine for protection against Proteus UTI and pyelonephritis.
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