ORCID

https://orcid.org/0000-0002-2361-2347

Date of Award

Summer 8-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Molecular Biophysics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Urinary tract infections (UTI) caused by uropathogenic Escherichia coli (UPEC) are common and highly recurrent. Two important non-behavioral risk factors for UTI in women are genetics and history of two or more episodes of previous UTI. However, specific mechanisms of how these two factors modulate host susceptibility to UTI remain unclear. Concordantly, inbred mice of various genotypes and with different infection histories exhibit different susceptibilities to acute and chronic bladder infection (cystitis), which recapitulates a range of clinical UTI outcomes observed in women. Early host-pathogen interactions have been shown to determine UTI outcomes in mouse models. Here, we used two strains of Juvenile Naive mice (no UTI history; C57BL/6J & C3H/HeOuJ), as well as previously infected C3H/HeN mice to identify shared patterns of gene expression that correlate with susceptibility to recurrent and chronic UTI.

Compared to adult C3H/HeN mice that had no prior UTI ("Adult Nave" mice), the disease outcomes of a prior infection in C3H/HeN mice: spontaneously resolved ("Resolved" mice) or develop chronic cystitis ("Sensitized" mice), dramatically separated their susceptibilities to subsequent infection: resistant or susceptible, respectively. Altered cell morphology, differentiation state, membrane proteomes, etc. have been revealed, suggesting remodeling of the urothelium by prior infections. This thesis investigates the transcriptomic profiles of C3H/HeN mice with different disease histories and corresponding susceptibility. Adult Nave and Resolved mice shared similar transcriptomes, while Sensitized mice displayed a distinct transcriptomic profile from Adult Nave (very) and Resolved (intermediate) mice. The differences in gene expression are mostly correlated with immune responses, cell morphology, and cell growth pathways. The results suggest that prior infections left persisting imprints at a transcriptional level that vary in susceptibility to subsequent challenge.

The transcriptomic profiles of mice were also investigated upon bladder infection. Juvenile Nave C57BL/6J mice and C3H/HeN Resolved were highly resistant to UPEC infection, whereas Juvenile Nave C3H/HeOuJ mice and C3H/HeN Sensitized were highly susceptible. Microscopic and cytokine analyses of infected bladders revealed differing kinetics of inflammation among mice with different genotypes and disease histories. Resistant mice (C57BL/6J) initiated a robust, early-onset (peaked at 6 hours post inoculation, but short-lasting inflammatory response, while the susceptible mice (C3H/HeOuJ) had an inverse pattern: robust, late-onset (peaked at 24 hpi), but persisting. Transcriptomic profiling of whole bladders revealed a specific dynamic pattern of TNF_ signaling that mirrored the degree and kinetics of this bladder inflammation. In convalescent C3H/HeN mice, prior infection resulted in an acquired capacity for robust to severe bladder inflammatory responses with a robust, early-onset TNF_. In contrast, age-matched C3H/HeN mice with no prior infection history had muted responses. Depletion of TNF_ in an rUTI model revealed that early TNF_ signaling promoted colonization resistance via exfoliation of infected bladder cells, but prolonged TNF_ signaling exacerbated inflammation, thereby worsening infection.

In summary, host susceptibility to severe and chronic cystitis are greatly impacted by the degree and kinetics of TNF_ signaling, which varies depending on host genetics and disease history.

Language

English (en)

Chair and Committee

Scott J. Hultgren

Committee Members

Maxim Artyomov, Michael G. Caparon, Jr, Daved H. Fremont, Thomas J. Hannan,

Comments

Permanent URL: 2020-08-09

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