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 one of the most common bacterial infections of humans and the most common kidney and urologic disease in the U.S. The most common uropathogen, Escherichia coli, can cause 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 are blocked by structural abnormality or urethral catheters, species such as Proteus mirabilis 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. We reason that there is a time to swim and a time to adhere; we also provide preliminary data that E. coli and P. mirabilis possess defined regulatory pathways by which they transform from the motile to the adherent form and wee versa. As well, other regulatory mechanisms have been uncovered. In this proposal, we will test the central hypothesis that uropathogenic E. coli and P. mirabilis regulate the balance between motility and adherence. We will test this hypothesis by carrying out the following specific aims: 1) Determine the mechanism of reciprocal control of motility and adherence; 2) Determine other mechanisms of flagella and fimbriae expression including coordinated expression, selection, and regulation by growth phase; and 3) Demonstrate in vivo the control of motility and adherence. Genetic constructs, molecular assays, microarrays, and a murine model of ascending urinary tract infection will be used to test the hypothesis. Determination of a defined mechanism has implications far beyond the urinary tract. Clearly the ability to colonize mucosal surfaces in the respiratory, intestinal, and genital tracts also require the orchestrated synthesis of fimbriae for adherence and flagella for motility.
Showing the most recent 10 out of 70 publications
