Biology and Biomedical Sciences: Molecular Microbiology and Microbial Pathogenesis
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Urinary tract infections: UTIs) affect 13 million women annually in the United States. Uropathogenic Escherichia coli: UPEC) is the predominant etiologic agent of UTI; however, several other uropathogens, including Klebsiella pneumoniae, are also significant causative agents. In a murine cystitis model, UPEC utilize a multistep pathogenic pathway in which they invade and form intracellular bacterial communities: IBCs) within bladder facet cells. Type 1 pili, adhesive fimbriae, are necessary for UPEC binding and invasion of urothelial cells and formation of IBCs. UPEC ultimately disperse from the IBC, many with filamentous morphology, and proceed to infect other host urothelial cells. This work evaluates the conservation of the IBC pathogenic pathway across both host and uropathogen. To determine if the IBC pathway occurs in human UTI, urine samples from women with acute, uncomplicated cystitis and from asymptomatic women were blindly analyzed. We found evidence of IBCs in 18% and filamentous bacteria in 41% of urines from women with UTI. None of the urines from the asymptomatic comparative group or from Gram-positive UTIs showed evidence of IBCs or filaments. These findings suggest that the IBC pathogenic pathway characterized in the mice also occurs in humans. Numerous non-UPEC, Gram-negative uropathogens were found competent for IBC formation in the murine cystitis model. The uropathogenesis of one of these IBC formers, K. pneumoniae, was compared to UPEC. K. pneumoniae was able to colonize the murine bladder and form IBCs, but to a lesser extent than UPEC early in infection. Much of this disparity can be attributed to differences in expression and function of type 1 pili. Specifically, K. pneumoniae encodes an extra fim operon gene, fimK, which inhibits expression of type 1 pili. Additionally, K. pneumoniae has a defect in the mannose-sensitive hemagglutination phenotype of type 1 pili specific to its FimH adhesin domain. These differences in expression and function of K. pneumoniae type 1 pili explain, in part, why K. pneumoniae is a less prevalent etiologic agent of UTI than UPEC. To further analyze host factors involved in UTI pathogenesis of K. pneumoniae and other uropathogens, we developed a streptozocin-induced diabetic model of UTI. Diabetic mice were found to be more susceptible to UTI, especially by non-UPEC uropathogens, compared to healthy mice. This work revealed that the IBC pathogenic pathway occurs in human UTI and is common to several uropathogens, albeit to varying degrees of efficiency. Further insight into this conserved pathway may lead to enhanced UTI treatments and prevention of recurrence.
Rosen, David, "Conservation Of The Intracellular Bacterial Community Pathogenic Pathway In Urinary Tract Infection" (2010). All Theses and Dissertations (ETDs). 299.