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Date of Award

Spring 5-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Clostridium difficile infection (CDI) is the most prevalent hospital-acquired infection, resulting in gastrointestinal disease with symptoms ranging from mild diarrhea to sepsis and death. Despite rising prevalence and severity, little is known regarding the mucosal immune response to CDI. Histologically the disease is characterized by marked neutrophilic infiltrate and fecal neutrophil chemokine expression correlates with disease severity. C. difficile-infected mice develop disease that closely mimics human CDI, including severe diarrhea, weight loss, intestinal epithelial injury, and tissue edema. We found there was a marked neutrophilic infiltrate that provided minimal survival benefit; instead, analysis of cecum, colon and mesenteric lymph nodes showed rapid production of IL-17A and IL-17F. Il17a-/-, but not Il17f-/- mice demonstrated more severe intestinal injury and increased mortality. While IL-17A is generally thought to protect mucosal surfaces through recruitment of neutrophils, we found that Il17a-/- animals had exacerbated neutrophilic infiltrate and increased expression of inflammatory mediators. However, expression of -defensins, but not -defensins, and monocyte influx were impaired in the intestines of Il17a-/- mice, identifying novel roles for this cytokine in mucosal immunity. During acute infection IL-17A was predominantly produced by T cells bearing V6 V1 and V2 V1 T cell receptors. These cells produced IL-17A and IL-17F in vitro upon exposure to IL-1 plus IL-23, while T cell receptor crosslinking provided further stimulation. Isolated IL-17A+ T cells expressed surface markers and transcription factors in a signature that is consistent with recent description of T17, cells imprinted in the embryonic thymus for rapid IL-17A production at mucosal surfaces. We find that humans with CDI have significantly elevated fecal IL17A and TRDV mRNA abundance, suggesting this ancient and highly conserved innate response may be protective in human patients with CDI.

Language

English (en)

Chair and Committee

David Haslam

Committee Members

Michael Caparon, David Hunstad, Celeste Morley, Thaddeus Stappenbeck, Philip Tarr

Comments

Permanent URL: http://dx.doi.org/10.7936/K7NK3C9Q

Available for download on Friday, May 15, 2116

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