Tissue Responses to Shiga Toxin in Human Intestinal Organoids

Pradhan, Suman; Karve, Sayali; Weiss, Alison A.; Hawkins, Jennifer; Poling, Holly M.; Helmrath, Michael A.; Wells, James M.; McCauley, Heather A.

doi:10.1016/j.jcmgh.2020.02.006

Cited by 32 publications

(47 citation statements)

References 52 publications

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“…We found that several of these genes, including JUN, FOS, CCL4, CXCL8, and IL1A were differentially expressed in WT vs ∆∆stx infected colons; thus, Stx by itself, in the absence of additional EHEC-derived factors may account for a subset of the transcriptional changes we identified in the colonic epithelium of animals infected with the WT strain. However, recent transcriptomic studies of the response of human intestinal organoids did not detect differential expression of many of the coagulation-associated or immune signaling genes (including F3, CXCL8, and IL23A) that we found in infected infant rabbits (47,51); these differences are potentially explained by organoid culture conditions, which can limit cytokine expression (82).…”

Section: Discussioncontrasting

confidence: 80%

“…The 'ribotoxic stress response' to Stx-mediated cellular damage leads to the upregulation of a variety of genes and production of proteins which modulate the immune response (23,25,26). Purified Stx promotes the production of transcription factors (including JUN and FOS) and inflammatory cytokines (CCL2, CCL3, CCL4, CCL5, CSF2, CSF3, CXCL1, CXCL2, CXCL3, CXCL5, CXCL8, IL10, IL1αβ, IL6, TNFα) in cultured epithelial and immune cells (42,41,43,22,40,29,(44)(45)(46)(47)26). We found that several of these genes, including JUN, FOS, CCL4, CXCL8, and IL1A were differentially expressed in WT vs ∆∆stx infected colons; thus, Stx by itself, in the absence of additional EHEC-derived factors may account for a subset of the transcriptional changes we identified in the colonic epithelium of animals infected with the WT strain.…”

Section: Discussionmentioning

confidence: 99%

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

Warr

Kuehl

Waldor

2020

Preprint

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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.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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

Warr

Kuehl

Waldor

2020

Preprint

View full text Add to dashboard Cite

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“…It is highly likely, though, that Stxs interfere with the signalling network between different cells in the immediate environment of STEC microcolonies in the bovine intestine including the targetting of a subset of EC. Such a concept of Stx toxicity depending on epithelial-mesenchymal cross-talk, in which mesenchymal cell damage causes epithelial cell damage, was recently described to characterize tissue responses to Stxs in human intestinal organoids [125].…”

Section: Intestinal Epithelial Cellsmentioning

confidence: 99%

The Role of Escherichia coli Shiga Toxins in STEC Colonization of Cattle

Menge

2020

Toxins

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Many cattle are persistently colonized with Shiga toxin-producing Escherichia coli (STEC) and represent a major source of human infections with human-pathogenic STEC strains (syn. enterohemorrhagic E. coli (EHEC)). Intervention strategies most effectively protecting humans best aim at the limitation of bovine STEC shedding. Mechanisms enabling STEC to persist in cattle are only partialy understood. Cattle were long believed to resist the detrimental effects of Shiga toxins (Stxs), potent cytotoxins acting as principal virulence factors in the pathogenesis of human EHEC-associated diseases. However, work by different groups, summarized in this review, has provided substantial evidence that different types of target cells for Stxs exist in cattle. Peripheral and intestinal lymphocytes express the Stx receptor globotriaosylceramide (Gb3syn. CD77) in vitro and in vivo in an activation-dependent fashion with Stx-binding isoforms expressed predominantly at early stages of the activation process. Subpopulations of colonic epithelial cells and macrophage-like cells, residing in the bovine mucosa in proximity to STEC colonies, are also targeted by Stxs. STEC-inoculated calves are depressed in mounting appropriate cellular immune responses which can be overcome by vaccination of the animals against Stxs early in life before encountering STEC. Considering Stx target cells and the resulting effects of Stxs in cattle, which significantly differ from effects implicated in human disease, may open promising opportunities to improve existing yet insufficient measures to limit STEC carriage and shedding by the principal reservoir host.

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“…Using HIOs exposed via luminal microinjection or basolateral addition to cell culture media, Pradhan et al demonstrated that purified Shiga toxin, Stx2a, disrupts epithelial barrier function after 48 hours, resulting in cell death via both necrosis and apoptosis. 37 Transcytosis of Stx2a across the epithelium occurred while the epithelial barrier was still intact within 24 hours. Pradhan et al also explored the effect of Stx2a on mesenchymalepithelial transition in the HIOs, an established response in wound healing.…”

Section: Enterohemorrhagic E Coli (Ehec)mentioning

confidence: 99%

Research in a time of enteroids and organoids: how the human gut model has transformed the study of enteric bacterial pathogens

et al. 2020

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Enteric bacterial pathogens cause significant morbidity and mortality globally. Studies in tissue culture and animal models shaped our initial understanding of these host-pathogen interactions. However, intrinsic shortcomings in these models limit their application, especially in translational applications like drug screening and vaccine development. Human intestinal enteroid and organoid models overcome some limitations of existing models and advance the study of enteric pathogens. In this review, we detail the use of human enteroids and organoids to investigate the pathogenesis of invasive bacteria Shigella, Listeria, and Salmonella, and noninvasive bacteria pathogenic Escherichia coli, Clostridium difficile, and Vibrio cholerae. We highlight how these studies confirm previously identified mechanisms and, importantly, reveal novel ones. We also discuss the challenges for model advancement, including platform engineering to integrate environmental conditions, innate immune cells and the resident microbiome, and the potential for pre-clinical testing of recently developed antimicrobial drugs and vaccines.

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Tissue Responses to Shiga Toxin in Human Intestinal Organoids

Cited by 32 publications

References 52 publications

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

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

The Role of Escherichia coli Shiga Toxins in STEC Colonization of Cattle

Research in a time of enteroids and organoids: how the human gut model has transformed the study of enteric bacterial pathogens

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