Degree Type

Dissertation

Date of Award

2009

Degree Name

Doctor of Philosophy

Department

Veterinary Pathology

First Advisor

Nancy A. Cornick

Second Advisor

Claire B. Andreasen

Abstract

Hemolytic uremic syndrome (HUS), a systemic complication of Shiga toxin-producing Escherichia coli (STEC) infection, is the number one cause of renal failure in children in the United States. At present, there is no known method to predict which patients with STEC infection will develop HUS and no effective treatment for the disorder once it is diagnosed. One of the primary barriers inhibiting development of an adequate therapy and/or preventative is an insufficient understanding of the intricate pathogenic cascade. It is known that Shiga toxin (Stx) is produced locally within the gastrointestinal tract, is absorbed into the systemic circulation by a yet undefined mechanism, binds to vascular endothelial cells expressing the Stx receptor. Stx is then internalized within the endothelial cell and interrupts protein synthesis, causing cell death. This endothelial cell injury causes microthrombi formation in key target organs (kidney, brain, colon) leading to the characteristic clinical triad of HUS: microangiopathic hemolytic anemia, thrombocytopenia, and acute renal damage. Although Stx is widely presumed to be the principal mediator of HUS, proinflammatory cytokines have been repeatedly implicated as substantial contributors to disease development. Stx induces cytokine production in a variety of cell types in vitro, and cytokines, in turn, greatly increase the sensitivity of endothelial cells to Stx. Several clinical studies have identified increased proinflammatory cytokines in patients with HUS compared to those with STEC-induced diarrhea alone. A more complete understanding of both toxin transport mechanisms and cytokine responses during HUS would aid in the development of treatment modalities; however, both the primary mode for toxin transport in vivo and the stimulus for cytokine alterations seen in HUS remain uncharacterized. Specifically, the role of Stx production and dissemination in proinflammatory cytokine alterations observed in clinically-affected patients has not been established. The goals of the studies outlined in this thesis were to: 1) clarify the role of Stx in modulating inflammation during STEC infection 2) identify specific interactions between Stx and neutrophils to assess the potential role of this leukocyte in Stx transport during STEC infection and 3) assess the efficacy of an oral Stx-binding agent at preventing systemic disease following STEC inoculation. To accomplish these goals, in vitro experiments, as well as in vivo experiments in an animal model of STEC infection, were used. The animal model chosen for the in vivo experiments was edema disease of swine, a naturally occurring STEC disease of weaned swine caused by host-adapted strains of E. coli that shares a similar pathogenesis with HUS.

Copyright Owner

Shannon Jones Hostetter

Language

en

Date Available

2012-04-29

File Format

application/pdf

File Size

128 pages

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