Role of Shiga toxin dissemination and inflammation in the pathogenesis of Shiga toxin-producing Escherichia coli infection

dc.contributor.advisor Nancy A. Cornick
dc.contributor.advisor Claire B. Andreasen
dc.contributor.author Hostetter, Shannon
dc.contributor.department Veterinary Pathology
dc.date 2018-08-11T12:58:17.000
dc.date.accessioned 2020-06-30T02:29:36Z
dc.date.available 2020-06-30T02:29:36Z
dc.date.copyright Thu Jan 01 00:00:00 UTC 2009
dc.date.embargo 2013-06-05
dc.date.issued 2009-01-01
dc.description.abstract <p>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.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/etd/10596/
dc.identifier.articleid 1615
dc.identifier.contextkey 2806782
dc.identifier.doi https://doi.org/10.31274/etd-180810-856
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath etd/10596
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/24802
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/etd/10596/Hostetter_iastate_0097E_10432.pdf|||Fri Jan 14 18:24:00 UTC 2022
dc.subject.disciplines Veterinary Pathology and Pathobiology
dc.subject.keywords Edema disease
dc.subject.keywords Escherichia coli
dc.subject.keywords Inflammation
dc.subject.keywords Neutrophil
dc.subject.keywords Shiga toxin
dc.subject.keywords Swine
dc.title Role of Shiga toxin dissemination and inflammation in the pathogenesis of Shiga toxin-producing Escherichia coli infection
dc.type article
dc.type.genre dissertation
dspace.entity.type Publication
relation.isOrgUnitOfPublication cf38d7e3-b5f8-4859-83e3-ae8fab6a4c5f
thesis.degree.level dissertation
thesis.degree.name Doctor of Philosophy
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