A highly synchronous murine model for EHEC infection reveals Shiga toxin promotes pathogen spread and systemic disease
Flowers, Laurice.
2017
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Abstract: Enterohemorrhagic Escherichia coli (EHEC) produces Shiga toxin, a phage-encoded toxin that is essential for triggering life-threatening hemolytic uremic syndrome and renal failure. How Stx targets the kidney and other extraintestinal tissues is poorly understood. EHEC does not efficiently colonized conventional mice, but gavage of mice with the related mouse pathogen, CR(stx), can cause ... read morea lethal systemic disease featuring renal damage. We previously generated a food-borne route of infection for CR(stx) that resulted in a highly synchronous disease model. This model allowed us to investigate the pathogenesis associated with EHEC disease. We show here that CR(stx), but not purified Stx, disrupts the intestinal barrier. The disruption in intestinal barrier function was associated with the spread of CR(stx) to extraintestinal tissues, importantly the kidney. Remarkably, the amount of Stx per CFU in kidney was 100-fold higher than that in the colon. However, high levels of Stx in the kidney that could not be achieved when CR(stx::kanR) inoculation was accompanied by a high dose of orally administered Stx. These findings indicate that the intestinal epithelium is an important target of Stx, resulting in the translocation of the pathogen to distant tissues. Further, the results suggest that renal failure, a major manifestation of EHEC infection, results from high levels of Stx produced by bacteria that have localized in the kidney after breakdown of the intestinal barrier. Targeting the reservoir of EHEC would benefit the entire populace because outbreaks are sporadic and seemingly unpredictable. Unfortunately, none of the current vaccines for cattle provide complete protection from fecal shedding or from colonization. Additionally, traditional methods of vaccination are not economically feasible for cattle operations. Therefore, we test our food-borne mouse model as a proof of principle model to investigate alternative vaccines. We show here that mice pre-infected with wild-type CR are protected from a lethal challenge of CR(stx). Additionally, we show that pre-infected mice produce a robust antibody response following CR(stx) challenge. Ultimately, these findings demonstrate the utility of our small animal model for testing alternative EHEC vaccines.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Molecular Microbiology.
Advisors: John Leong, and Joan Mecsas.
Committee: Cheleste Thorpe, Abraham Sonenshein, Ralph Isberg, and Cammie Lesser.
Keyword: Microbiology.read less - ID:
- js956s66n
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