Urinary tract infections (UTI) are a common occurrence. Uncomplicated UTI happen when specialized bacterial pathogens gain access to the bladder of otherwise healthy individuals, and are predominantly caused by a subset of Escherichia coli called uropathogenic E. coli. However, patients with urinary catheters or abnormalities of the urinary tract are highly susceptible to bacterial infections, or complicated UTI. One major contributor to complicated UTI is the Gram-negative species Proteus mirabilis.
P. mirabilis is capable of moving across solid surfaces (including urinary catheters) in large, coordinated blocs of cells, in a specialized process called swarming (figure). P. mirabilis, like many bacteria, also swims through liquids; both swarming and swimming require whip-like appendages called flagella. Once in the urinary tract, P. mirabilis produces urease, which raises urinary pH and leads to stone formation. This bacterium is also able to adhere to host cells lining the urinary tract using protein structures called fimbriae. The P. mirabilis genome potentially encodes 17 unique fimbriae, suggesting that adherence to multiple surfaces contributes to the survival strategy of this species. Many of the fimbrial gene clusters also include a regulatory gene which, when highly expressed, represses flagella (and therefore motility). Thus, P. mirabilis may stick or swim, by controlling which system (fimbriae or flagella) is expressed. The current focus of the Pearson lab is to study these largely uncharacterized fimbriae and fimbria-associated regulators in greater detail.
1. What is the role of fimbriae produced by P. mirabilis? Do all 17 fimbrial operons produce intact fimbriae? When are they expressed, and how many contribute to UTI? What are the targets for these fimbriae? How conserved are these fimbriae in different P. mirabilis isolates? At this time, only 5 of the 17 fimbriae have been studied at any level. One fimbria, the mannose-resistant/Proteus-like (MR/P) fimbria, is predominantly expressed during a mouse model of urinary tract infection, although others contribute to infection or colonization. The host target has not been identified for any of these fimbriae, including MR/P. A range of approaches will be used to study these fimbriae, including PCR and real-time PCR, Western blotting, mutagenesis, and assessment of host response during experimental UTI.
2. What is the role of the fimbria-associated transcriptional regulators? The first gene of this class of regulators to be studied, mrpJ, was found to repress bacterial motility when overexpressed. However, there are 14 additional paralogs of mrpJ in the P. mirabilis genome. When overexpressed, most of them repress motility, but they do not all repress to the same degree and cause distinct abnormalities in swarm behavior. Thus, although MrpJ binds to the promoter of the flagellar master regulator flhDC, this is not necessarily the case for the other genes in this class. There is also some evidence for fimbrial regulation of other fimbriae via MrpJ paralogs. Microarrays, cloning, and mutagenesis will be used to answer these questions.
Adjunct Assistant Professor, Department of Microbiology
Fellowship, University of Michigan Medical School, Genomic Characterization of Proteus mirabilis
PhD from University of Texas at Austin
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