Date of Award

Summer 8-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Urinary tract infections (UTI) affect over 150 million individuals worldwide every year. These infections are associated with significant morbidity and have a sizeable economic impact, with $5 billion being spent on UTI treatment in the USA annually. Uropathogenic E. coli (UPEC) are responsible for 80% of community acquired UTIs and 65% of nosocomial UTI. The current standard of care for UTI is antibiotic therapy. However, 30-50% of women experience recurrent UTI (rUTI) despite receiving antibiotic therapy. The prevalence of single and multi-drug resistant UPEC strains has led to increased reliance on carbepenems, which are primarily reserved for multi-drug resistant infections, to treat an increasing number of patients. Consequently E. coli strains resistant to colistin, a drug of last resort for treating carbapenem-resistant Enterobacteriaceae, have now been isolated in over 30 counties. The rate at which drug-resistant E. coli are spreading across the globe emphasizes the urgent nature of the antibiotic-resistance crisis we currently face and the dire need for new, antibiotic-sparing therapies that target UPEC virulence factors. To colonize host tissue, E. coli encode chaperone usher pathway (CUP) pili and single UPEC strains can encode up to 16 distinct CUP pilus operons. Although CUP pilus types that promote UPEC colonization of the urinary tract have been identified, no studies investigating a role for CUP pilus types in UPEC intestinal colonization have been published. Still, leading models of infection posit that UPEC in the gut seed UTI by being shed in the feces, and then colonizing the peri-urethral or vaginal tissue and subsequently ascending through the urethra to access the bladder. Using a mouse model of UPEC intestinal colonization I found that two (CUP) pili, F17-like pili and type 1 pili, provide a fitness advantages for UPEC in the gut. The X-ray crystal structure of the F17-like pilus adhesin lectin domain, coupled with molecular studies of glycan binding, disclosed a ligand specificity distinct from other pilus types known to facilitate gastrointestinal colonization. While phylogenomic studies revealed that F17-like pili are closely related to pilus types carried by intestinal pathogens, but are restricted to extra-intestinal pathogenic E. coli. Moreover, I found that high-affinity mannose analogues (mannosides) that target the function of type 1 pili and effectively treat UTI reduce intestinal colonization by clinical UPEC isolates, including a multi-drug resistant strain, without disrupting gut microbiota structure. By decreasing the intestinal UPEC reservoir that seeds bladder infection, mannosides could significantly reduce the rate of UTI and rUTI. Further, mannosides act like a molecular scalpel, specifically targeting intestinal UPEC with minimal effects on the overall gut microbiota. Ultimately, therapies like mannosides, which selectively target colonization by a specific pathogen, have potential to revolutionize treatment and prevention of rUTI. Take together, this dissertation provides invaluable tools and insights into the understudied UPEC intestinal reservoir.

Language

English (en)

Chair and Committee

Scott J. Hultgren

Committee Members

John Atkinson, Brian Edelson, Jeffrey I. Gordon, David Hunstad,

Comments

Permanent URL: https://doi.org/10.7936/K7FN15NS

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