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dc.contributor.advisorStearns-Kurosawa, Deborah J.en_US
dc.contributor.authorHall, Gregoryen_US
dc.date.accessioned2019-01-04T16:50:37Z
dc.date.available2019-01-04T16:50:37Z
dc.date.issued2018
dc.identifier.urihttps://hdl.handle.net/2144/33001
dc.description.abstractShiga toxin-producing E. coli (STEC) are globally relevant bacterial pathogens responsible for epidemic outbreaks of hemorrhagic diarrhea with variable progression to potentially fatal systemic Shiga toxicosis. Predictive clinical biomarkers and targeted therapeutic interventions for systemic Shiga toxicosis in diagnosed STEC patients are not available, and the impact of Shiga toxin production on STEC colonization and survival remain unclear. Improved murine models of STEC infection are needed to address knowledge gaps surrounding the gastrointestinal effects of Shiga toxins, as previously published models utilize ablation of host defense responses or microbiota depletion to facilitate colonization and are poorly suited for study of the effects of Shiga toxins on host responses. Dextran sulfate sodium (DSS) colitis in rodents has been associated with outgrowths of commensal E. coli in the literature, suggesting that DSS colitis could open a gastrointestinal niche usable by pathogenic STEC. This DSS colitis-based approach successfully induced susceptibility to robust colonization by two clinical isolate STEC strains in standard C57BL/6 mice. Studies using a Shiga-like toxin 2 (STX2)-producing clinical isolate STEC strain and its paired isogenic STX2 deletion strain (STEC(ΔSTX2)) revealed that STX2 was associated with delayed gastrointestinal clearance of STEC and concurrent reduction in colonic interleukin 23 (IL-23) axis transcripts known to be critical for pathogen clearance in other gastrointestinal pathogen models. In vivo reductions in IL-23 axis transcripts in the DSS+STEC model were supported by decreased IL-23 protein secretion by human macrophage-like cells during Shiga intoxication in vitro. Increased morbidity during STX2-producing STEC infection was associated with renal injury consistent with murine systemic Shiga toxicosis characterized by elevations in renal transcripts of molecular injury markers and histologically apparent renal tubular injury in a subset of mice. The dissertation research establishes a novel model of DSS colitis-facilitated murine STEC infection that recapitulates progression to systemic Shiga toxicosis in a subset of infected mice and demonstrates a clear STEC survival benefit associated with STX2 production. Shiga toxin-induced suppression of IL-23 axis signaling is a novel finding facilitated by the DSS+STEC model, demonstrating its utility for future delineation of the impacts of Shiga toxins on gastrointestinal host responses to STEC.en_US
dc.language.isoen_US
dc.rightsAttribution 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectPathologyen_US
dc.subjectEHECen_US
dc.subjectInterleukin 23en_US
dc.subjectShiga toxin-producing E. colien_US
dc.subjectShiga toxinsen_US
dc.subjectSTECen_US
dc.titleDextran sulfate sodium colitis facilitates murine colonization by Shiga toxin-producing E. coli: a novel model for the study of Shiga toxicosisen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2018-10-24T22:03:23Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplinePathologyen_US
etd.degree.grantorBoston Universityen_US


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International