Date of Award

Spring 5-15-2018

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 (UTIs) are among the most common bacterial infections which plague humans. Community-onset UTI is widely viewed as a disease only of women; indeed, its occurrence between 2 and 60 years of age is almost exclusive to females. However, the disease also affects substantial male patient populations, namely infants and the very elderly. While female cases of complicated and upper-tract UTI (pyelonephritis) outnumber male cases overall, men carry an increased risk of mortality from these infections. Sex differences in UTI epidemiology have heretofore been attributed almost entirely to anatomic and hygienic factors in females, including the permissiveness of surrounding environments to microbial colonization, shorter urethral length, and shorter distance from anus to the urethral meatus. However, these hypotheses and potential mechanisms driving sex differences in UTI have not been investigated due to a lack of preclinical models allowing sex comparisons.

In response to this deficit, we devised a minimally invasive surgical bladder inoculation technique that yields reproducible upper and lower UTI in both male and female mice. Acute uropathogenic Escherichia coli (UPEC) infection in males of two mouse strains recapitulated the intracellular bacterial community pathway previously shown in females. Compared with females, C3H/HeN males displayed a striking predilection for chronic cystitis, manifesting as persistent bacteriuria, high-titer bladder bacterial burdens, and chronic inflammation as previously characterized in catheter-infected C3H/HeN females. Further, males developed more severe pyelonephritis, as well as nearly 100% penetrant renal abscesses, a complication that is rare in female mice. Within the abscess, UPEC formed a dense nidus of intratubular, biofilm-like communities that appeared sheltered from surrounding inflammatory cells by a fibrotic capsule. The formation of these abscess communities required type 1 pili, a major urovirulence determinant in the bladder but not previously implicated in pyelonephritis.

Severe ascending UTI in males was sharply abrogated following castration, but complemented with exogenous testosterone. Similarly, administration of exogenous testosterone in C3H/HeN females imparted susceptibility to severe pyelonephritis and abscess formation. Susceptibility to severe UTI was also induced in both sexes with 5-α-dihydrotestosterone or attenuated by treatment with the antiandrogen flutamide. Further, male mice lacking a functional androgen receptor were protected from severe upper-tract UTI. Collectively, these data show that specific activation of the androgen receptor augments severity of UTI in both sexes.

Our mini-surgical model provides a new preclinical platform for translatable studies of UTI pathogenesis in both male and female hosts, specifically expanding studies of pyelonephritis, ascending renal abscess development, and the treatment of complicated UTI. The discovery of intratubular UPEC communities in this model offers a first look at early renal abscess pathogenesis and helps to explain the need for prolonged antimicrobial treatment during severe pyelonephritis. Further, our findings suggest that modulation of androgens may represent a novel therapeutic route to combat recalcitrant or recurrent UTI, and may help to explain why certain patient populations are more likely to develop UTI.

Language

English (en)

Chair and Committee

David A. Hunstad

Committee Members

Michael G. Caparon, Keith A. Hruska, Scott J. Hultgren, Kelle H. Moley,

Comments

Permanent URL: https://doi.org/10.7936/K71835Z2

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