Date of Award

Winter 12-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Urinary tract infections (UTIs) are common diseases that are associated with significant morbidities. Multiple studies have indicated that multiple species of uropathogenesis bacteria invade and persist within bladder epithelial cells as a necessary step of uropathogenesis. Interestingly, many of these species are not canonically associated with intracellular infections. Although the first study describing bacteria within the urothelium was published two decades ago, this critical step of uropathogenesis remains relatively understudied.

I established a murine model of community-acquired A. baumannii UTI, a previously unstudied manifestation of the disease. While immunocompetent mice resolved their infections quickly, immunocompromised mice displayed high bacterial burdens throughout their urinary tracts for several weeks. I found that mice infected using this model retained A. baumannii intracellular reservoirs (ABIRs) in their urothelium long after the resolution of the initial colonization event. Inserting a catheter into the bladders of these resolved mice triggered a same-strain UTI in over 50% of the mice. Stringent experimental controls suggest that these resurgences came from bacterial reservoirs within the resolved host. Further testing implicates the ABIRs as the most likely source.

I have also characterized the intracellular phenotypes of multiple uropathogenic E. coli (UPEC) clinical isolates. While each isolate had unique strain-specific characteristics, all three of the phylogroup A strains proved to be incapable of properly undergoing the intracellular steps of uropathogenesis. I have also studied an important process used by intracellular UPEC, lactose metabolism. UPEC isolates with mutations in their lac operons formed significantly smaller intracellular bacterial communities, and were unable to complete IBC development. However, I found that UPEC strains with deficient lactose permeases were still capable of importing lactose-like sugars.

Overall, my dissertation contributes to field of intracellular uropathogenesis in multiple ways. With E. coli, I have identified a potential link between bacterial genetics, specifically when a bacterium is a member of phylogroup A, and intracellular phenotype in the bladder. I have also established that lacY-deficient UPEC isolates are capable of internalizing lactose-like sugars, which suggests the presence of a secondary mechanism. I have also developed a murine model of community-acquired UTI for A. baumannii and have investigated both the pathogenesis and the prevalence of this manifestation. I have also developed the first murine model of resurgent infections for A. baumannii and have identified a potential reservoir bringing novel strains into the hospital in the form of host reservoirs. Previous Acinetobacter UTI research has focused primarily on complicated UTIs. Together, my findings expand our knowledge of Acinetobacter uropathogenesis in the previously unstudied, community-acquired model of infection.

Language

English (en)

Chair and Committee

Scott J. Hultgren

Committee Members

Mario Feldman, David Hunstad, Michael Caparon, Heather Lawson,

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