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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) are extremely common and can be highly recurrent: in women the lifetime incidence is greater than 50%, and 25% of women with an acute UTI will experience a recurrent episode within six months. A prior history of UTI is one of the single biggest independent risk factors for developing an acute UTI. However, history of UTI is rarely incorporated into animal models, and our knowledge of the bacterial mechanisms and host determinants of UTI pathogenesis has come largely from studies of naive mice. About 80% of uncomplicated UTI are caused by uropathogenic Escherichia coli (UPEC), and for my dissertation I have developed mouse models to address two possible sources of recurrent UPEC UTI. These studies harness the inherent differences in UTI susceptibility seen in different inbred mouse strains.

First, I have found that in inbred C3H/HeN mice, chronic UPEC infection “remodels” the bladder epithelium, causing changes to the tissue that persist even after antibiotic therapy. I showed that bladder remodeling enhances host susceptibility to recurrent UTI caused by diverse uropathogens, including multi drug-resistant strains. However, targeting the host immune response by vaccination or anti-inflammatory drugs could prevent recurrent UTI. Second, I have helped develop a recurrent UTI model in inbred C57BL/6 mice, which do not develop chronic UPEC infection; instead, after an initial acute infection, UPEC can establish dormant reservoirs deep within the bladder epithelium that can emerge in response to unknown triggers. In this model we found that bladder exposure to the harmful vaginal bacterium Gardnerella vaginalis (which, in women with a vaginal dysbiosis known as bacterial vaginosis, is a likely consequence of sexual activity) caused exfoliation and the emergence of dormant E. coli reservoirs, leading to recurrent UPEC UTI. These mouse models have led to a new understanding of the impact of host history of infection on UTI risk, and can inform future drug development.

Language

English (en)

Chair and Committee

Scott Amanda J. Hultgren Lewis

Committee Members

John P. Atkinson, Brian T. Edelson, David A. Hunstad, L D. Sibley,

Comments

Permanent URL: https://doi.org/10.7936/K7Q52P2D

Available for download on Wednesday, August 02, 2119

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Microbiology Commons

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