Molecular mechanisms of uropathogenesis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): The urinary tract is a complicated epithelial-lined tube with an opening to the body surface, making it susceptible to infection by exogenous organisms. Indeed, urinary tract infection is the second most common bacterial infection of humans and the most common kidney and urologic disease in the U.S. The most common uropathogen, Escherichia coli, causes acute cystitis or pyelonephritis in the uncomplicated urinary tract. On the other hand, in patients with complicated urinary tracts, ones in which normal urine flow is blocked by structural abnormality or urethral catheters, Proteus mirabilis may predominate. Both E. coli and P. mirabilis are members of the Enterobacteriaceae, are motile, and produce a battery of fimbriae by which they mediate adherence to the uroepithelium. The abilities to swim using flagella and to adhere by certain fimbriae have been demonstrated to be virulence traits for both organisms. However the actions of the two organelles have opposite functions and should not be employed at the same time. We have provided significant evidence and developed the theme that E. coli and P. mirabilis possess defined regulatory pathways by which they transition from the adherent to the motile form and display unique phenotypes associated with each lifestyle. Genes expressed during these opposite lifestyles govern the biology of infection of the urinary tract. Terminal genes in adherence gene operons of both pathogens have been demonstrated to specifically repress motility. However, when these phase variable fimbrial operons are in the off phase, flagella are expressed. In P. mirabilis, MrpJ (a PapX homolog) encoded by the MR/P fimbrial operon, inhibits swarming. When MR/P fimbriae are phase off, P. mirabilis differentiates into highly motile swarmer cells and induces a type 6 secretion system to kill competitors. In E. coli, the P fimbrial operon gene product PapX and the non-fimbrial TosA operon gene products TosE and TosF repress flagellar synthesis. These compelling phenotypes will be the subject of investigation. In this proposal, we will advance the central hypothesis that uropathogenic E. coli and P. mirabilis regulate adherence and motility resulting in distinct patterns of gene expression that are advantageous during infection of the urinary tract. We will test this hypothesis by carrying out the following specific aims: 1) Determine the mechanism of interbacterial killing by the swarming-induced type VI secretion system in Proteus mirabilis. 2) Determine the mechanism of repression of motility by regulatory genes in the pap and tos adherence operons in uropathogenic E. coli. This contribution will be significant because two of the principal virulence properties of E. coli and P. mirabilis are adherence and motility. Understanding the mechanisms by which these species regulate these critical traits and defining the phenotypes associated with each phase will advance our knowledge of these pathogens. By implementing our specific aims, we will elucidate regulatory pathways that govern two critical functions, motility and adherence, which will provide the opportunity to identify novel targets for development of new antimicrobial agents.