Date of Award
10-16-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
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.
Language
English (en)
Chair and Committee
Andrew Kau
Committee Members
Ali Ellebedy; Brian Laidlaw; David Hunstad; James Fleckenstein; Scott Hultgren
Recommended Citation
Santiago Borges, Jesus Miguel, "Novel Strategies to Target Uropathogenic Escherichia coli in the Bladder and Gut" (2024). Arts & Sciences Electronic Theses and Dissertations. 3272.
https://openscholarship.wustl.edu/art_sci_etds/3272