Abstract

Urinary tract infections (UTIs) pose significant challenges due to rising antibiotic resistance, demanding the development of antibiotic-sparing treatment approaches. Uropathogenic Escherichia coli (UPEC) is the major cause of UTIs and relies on the type 1 pili (T1P) adhesin, FimH, to cause bladder infection and establish a reservoir in the gut. In this thesis, we developed a mucosal vaccine targeting FimH that has shown great promise at modulating gut colonization by UPEC. The effectiveness of FimH vaccination at clearing UPEC from the gut was influenced by microbial competition from the gut microbiota and isogenic UPEC strains. This competition resulted in partial restriction of incoming UPEC strains to the mucus layer, where immunization was associated with reduced expression of the T1P. Additionally, in this thesis, we generated cross-reactive monoclonal antibodies (mAbs) against the lectin domain of FimH of UPEC and Klebsiella pneumoniae, common causative agents of UTIs. These FimH-mAbs were characterized using in vitro assays to gage their potential to inhibit T1P function and imaged using cryo-EM to identify epitopes of interest. Some of these FimH-mAbs showed significant prophylactic protection in mouse models of UTIs. Altogether, the studies conducted as part of this thesis pave the way for many other research venues in the UTI and microbiome research fields and get us closer to developing more comprehensive strategies to treat and prevent UTIs.

Committee Chair

Andrew Kau

Committee Members

Ali Ellebedy; Brian Laidlaw; David Hunstad; James Fleckenstein; Scott Hultgren

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

10-16-2024

Language

English (en)

Download

Available for download on Tuesday, December 17, 2030

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Biology Commons

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