Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli

Warr, A. R.; Kuehl, C. J.; Waldor, M. K.

doi:10.1101/2020.08.11.245555

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bioRxiv · 10.1101/2020.08.11.245555

Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli

Warr, A. R.·Kuehl, C. J.·Waldor, M. K.

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Abstract

Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that causes diarrheal disease and the potentially lethal hemolytic uremic syndrome. We used an infant rabbit model of EHEC infection that recapitulates many aspects of human intestinal disease to comprehensively assess colonic transcriptional responses to this pathogen. Cellular compartment-specific RNA-sequencing of intestinal tissue from animals infected with EHEC strains containing or lacking Shiga toxins (Stx) revealed that EHEC infection elicits a robust response that is dramatically shaped by Stx, particularly in epithelial cells. Many of the differences in the transcriptional responses elicited by these strains were in genes involved in immune signaling pathways, such as IL23A, and coagulation, including F3, the gene encoding Tissue Factor. RNA FISH confirmed that these elevated transcripts were found almost exclusively in epithelial cells. Collectively, these findings suggest that within the intestine, Stx primarily targets epithelial cells, and that the potent Stx-mediated modulation of innate immune signaling skews the host response to EHEC towards type 3 immunity. Significance StatementEnterohemorrhagic Escherichia coli (EHEC) is a potentially lethal foodborne pathogen. During infection, EHEC releases a potent toxin, Shiga toxin (Stx), into the intestine, but there is limited knowledge of how this toxin shapes the host response to infection. We used an infant rabbit model of infection that closely mimics human disease to profile intestinal transcriptomic responses to EHEC infection. Comparisons of the transcriptional responses to infection by strains containing or lacking Stx revealed that this toxin markedly remodels how the epithelial cell compartment responds to infection. Our findings suggest that Stx biases the intestinal innate immune response to EHEC and provide insight into the complex host-pathogen dialogue that underlies disease.

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Warr, A. R., Kuehl, C. J., Waldor, M. K.. 2020-08-11. Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli. https://doi.org/10.1101/2020.08.11.245555

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