Tissue responses to Shiga toxin in human intestinal organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA604235 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10995943.fastq.gz | Fastqsanger.gz | |||
| SRR10995944.fastq.gz | Fastqsanger.gz | |||
| SRR10995945.fastq.gz | Fastqsanger.gz | |||
| SRR10995946.fastq.gz | Fastqsanger.gz | |||
| SRR10995947.fastq.gz | Fastqsanger.gz |
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Project description:Intestinal tissue responses to protein synthesis inhibition by Shiga toxin are complex. Organoid models allow for an unprecedented examination of human tissue responses to a deadly Shiga toxin.
2020-02-01 | GSE144633 | GEO
Project description:Background & aimsShiga toxin (Stx)-producing Escherichia coli (eg, O157:H7) infection produces bloody diarrhea, while Stx inhibits protein synthesis and causes the life-threatening systemic complication of hemolytic uremic syndrome. The murine intestinal tract is resistant to O157:H7 and Stx, and human cells in culture fail to model the complex tissue responses to intestinal injury. We used genetically identical, human stem cell-derived intestinal tissues of varying complexity to study Stx toxicity in vitro and in vivo.MethodsIn vitro susceptibility to apical or basolateral exposure to Stx was assessed using human intestinal organoids (HIOs) derived from embryonic stem cells, or enteroids derived from multipotent intestinal stem cells. HIOs contain a lumen, with a single layer of differentiated epithelium surrounded by mesenchymal cells. Enteroids only contain epithelium. In vivo susceptibility was assessed using HIOs, with or without an enteric nervous system, transplanted into mice.ResultsStx induced necrosis and apoptotic death in both epithelial and mesenchymal cells. Responses that require protein synthesis (cellular proliferation and wound repair) also were observed. Epithelial barrier function was maintained even after epithelial cell death was seen, and apical to basolateral translocation of Stx was seen. Tissue cross-talk, in which mesenchymal cell damage caused epithelial cell damage, was observed. Stx induced mesenchymal expression of the epithelial marker E-cadherin, the initial step in mesenchymal-epithelial transition. In vivo responses of HIO transplants injected with Stx mirrored those seen in vitro.ConclusionsIntestinal tissue responses to protein synthesis inhibition by Stx are complex. Organoid models allow for an unprecedented examination of human tissue responses to a deadly toxin.
| S-EPMC7240222 | biostudies-literature
Project description:Shiga-toxin producing Enterotoxigenic Escherichia coli
| PRJEB25657 | ENA
Project description:Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that causes diarrheal disease and the potentially lethal hemolytic uremic syndrome. Here, we used an infant rabbit model of EHEC infection that recapitulates many aspects of human intestinal disease to comprehensively assess the host colonic epithelial and lamina propria cell transcriptional responses to EHEC infection. Furthermore, comparisons of colonic pathology and intestinal transcriptomic profiles in animals infected with EHEC strains containing or lacking Shiga toxins (∆∆stx) were carried out to investigate how these potent toxins shape the host response to the pathogen. We found that Stx is required for severe, multi-focal hemorrhage and extensive apoptosis in the colon. RNA-sequencing revealed that EHEC infection elicits a robust innate immune response in the colonic epithelium that is dramatically shaped by Stx. Over 1400 genes were differentially expressed in animals infected with WT versus ∆∆stx EHEC strains. Several pathways linked to innate immune responses were dependent on Stx. Upregulated genes in the presence of toxin included cytokines IL23a and CXCL8, as well as F3, the gene encoding the coagulation initiator Tissue Factor. RNA FISH revealed that these elevated transcripts were found almost exclusively in epithelial cells, suggesting that Stx remodels the transcriptional profile of the epithelium. Collectively, these findings reveal that Stx potently modulates the innate immune response to EHEC in the intestine, and suggest that Stx drives the response to infection towards type 3 immunity.
2021-01-14 | GSE156056 | GEO
Project description:Changes in endothelial phenotype induced by E. coli-derived Shiga toxins (Stx) are believed to play a critical role in the pathogenesis of hemolytic uremic syndrome. Stx inactivate host ribosomes, but also alter gene expression at concentrations that minimally affect global protein synthesis. The effect of Stx on the gene expression profile of human microvascular endothelial cells was examined using the Affymetrix HG-U133A platform. Data were processed using 13 different methods and revealed 369 unique differentially expressed genes, 318 of which were up-regulated and 51 of which were down-regulated. These studies implicated activation of the CXCR4/CXCR7/SDF-1 chemokine pathway in Stx-mediated pathogenesis. Primary human dermal microvascular endothelial cells were treated with vehicle or Shiga toxin (10 fM, 24 h, n = 6) and changes in steady-state mRNA levels were determined by hybridization to Affymetrix HG-U133A arrays
2011-10-10 | E-GEOD-32710 | biostudies-arrayexpress
Project description:The retrograde transport inhibitor Retro-2 has a protective effect on cells and in mice against Shiga-like toxins and ricin. Retro-2 causes toxin accumulation in early endosomes, and the relocalization of the Golgi SNARE protein syntaxin-5 to the endoplasmic reticulum. The molecular mechanisms by which this is achieved remain unknown. Here, we show that Retro-2 targets the endoplasmic reticulum exit site component Sec16A, affecting anterograde transport of syntaxin-5 from the endoplasmic reticulum to the Golgi. The formation of canonical SNARE complexes involving syntaxin-5 is not affected in Retro-2-treated cells. In contrast, the interaction of syntaxin-5 with a newly discovered binding partner, the retrograde trafficking chaperone GPP130, is abolished, and we show that GPP130 must indeed bind to syntaxin-5 to drive Shiga toxin transport from endosomes to the Golgi. We thereby identify Sec16A as a druggable target, and provide evidence for a non-SNARE function for syntaxin-5 in interaction with the retrograde cycling protein GPP130. a) Clickable Retro-2 pulldown. To identify protein target of Retro-2.1, providing the first steps to explain effects of Retro-2 on inhibition of STxB retrograde trafficking from endosomes to Golgi. b) GFP-STX5 pulldown. To find interactors of STX5, to build a hypothesis to explain the affect of Retro-2-inhibited anterograde trafficking of STX5 to Golgi, which in turn inhibits STxB retrograde transport from endosomes to Golgi. c) GFP-Sec16A pulldown. The aim of this proteomics assay is to show the effects of Retro-2 on the Sec16A interactome. Results show the differential effects of Retro-2 treatment on the Sec16A interactome, giving insight into the mechanism by which Retro-2, via Sec16A, specifically affects the anterograde trafficking of Syntaxin-5.
2020-02-24 | PXD015642 | Pride
Project description:The microarray data provided here belong to a study that describes two different Shiga toxin (Stx) induced models of hemolytic uremic syndrome (HUS) in mice. Although several rodent models of HUS were published, it still remains difficult to reproduce all clinical features of human HUS. Here, two different Stx2 regimes combined with volume resuscitation were tested in C57BL/6J wild type mice. Animals were euthanized because of kidney injury after 3 or 7 days respectively. Kidneys were removed for histological evaluation and RNA extraction. Kidney injury was confirmed histologically and by laboratory parameters in plasma. Data for the respective vehicle treated groups are also provided here.
2017-10-01 | GSE99229 | GEO
Project description:Infection with Shiga toxin (Stx) producing Escherichia coli O157:H7 can cause the potentially fatal complication hemolytic uremic syndrome, and currently only supportive therapy is available. Lack of suitable animal models has hindered study of this disease. Induced human intestinal organoids (iHIOs), generated by in vitro differentiation of pluripotent stem cells, represent differentiated human intestinal tissue. We show that iHIOs with addition of human neutrophils can model E. coli intestinal infection and innate cellular responses. Commensal and O157:H7 introduced into the iHIO lumen replicated rapidly achieving high numbers. Commensal E. coli did not cause damage, and were completely contained within the lumen, suggesting defenses, such as mucus production, can constrain non-pathogenic strains. Some O157:H7 initially co-localized with cellular actin. Loss of actin and epithelial integrity was observed after 4 hours. O157:H7 grew as filaments, consistent with activation of the bacterial SOS stress response. SOS is induced by reactive oxygen species (ROS), and O157:H7 infection increased ROS production. Transcriptional profiling (RNAseq) demonstrated that both commensal and O157:H7 upregulated genes associated with gastrointestinal maturation, while infection with O157:H7 upregulated inflammatory responses, including interleukin 8 (IL-8). IL-8 is associated with neutrophil recruitment, and infection with O157:H7 resulted in recruitment of human neutrophils into the iHIO tissue.
| S-EPMC5470682 | biostudies-literature
Project description:Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli
| PRJNA656553 | ENA
Project description:Enterohaemorrhagic E. coli is significant human pathogen that causes disease ranging from haemorrhagic colitis to haemolytic uremic syndrome. The later can lead to potentially fatal renal failure and is caused by the release of Shiga toxins that are encoded within lambdoid bacteriophages. The toxins are encoded within the late transcript of the phage and are regulated by anti-termination of the PR’ late promoter during lytic induction of the phage. During lysogeny, the late transcript is prematurely terminated at tR’ immediately downstream of PR’, generating a short RNA that is a by-product of anti-termination regulation. We demonstrate that this short transcript binds the small RNA chaperone Hfq, and is processed into a stable 74 nt regulatory small RNA that we have termed, StxS. StxS activates expression of the general stress response sigma factor, RpoS, through direct interactions with an activating seed sequence within the 5’ UTR. StxS represses expression of Shiga toxin 1 and activation of RpoS promotes high cell density growth under nutrient limiting conditions. Many phages utilise anti-termination to regulate the lytic/lysogenic switch and our results demonstrate that short RNAs generated as a by-product of this regulation can acquire regulatory small RNA features and modulate host fitness.
2020-09-16 | GSE143631 | GEO