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Chapter 5 : Role of Shiga/Vero Toxins in Pathogenesis

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Role of Shiga/Vero Toxins in Pathogenesis, Page 1 of 2

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Abstract:

It is generally accepted that all actions of Shiga toxin (Stx) depend on its interaction with the receptor, globotriaosylceramide (Gb), on eukaryotic cells. Although alternative receptors for Stx have been postulated, no definitive data have been forthcoming in support. Stx holotoxin is internalized by receptor-mediated endocytosis, retrograde transported via the Golgi apparatus and processed through in the endoplasmic reticulum, and released into the cytoplasm where it enzymatically inactivates ribosomes and inhibits protein synthesis ( Fig. 1 ). However, it is important to note that, in addition to Stx holotoxin, the B-subunit alone can interact with Gb in a physiologically meaningful manner where it activates signal transduction pathways in target cells ( Fig. 1 ) ( ). An additional but unexplained anomaly is the interaction of Stx with eukaryotic cells in a Gb-independent manner that leads to induction of cytokines by these cells ( ). As shown in Fig. 1 , intracellular responses to Stx are diverse, including inhibition of protein synthesis, activation of cellular stress responses, and induction of cytokines and chemokines. It is likely that these different schemes take place in cell-specific activities during Shiga toxin-producing (STEC) infections in humans, culminating in typical hemolytic-uremic syndrome (HUS). As depicted, it is clear that in some cases Stx can result in activation of p38 mitogen-activated protein kinase as well as apoptotic and necrotic cell death ( Fig. 1 ). The topic of HUS renal disease has been reviewed recently ( ).

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Figure 1

Schema: Shiga toxin interaction with eukaryotic cells.

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Figure 2

Proposed pathways of Stx and LPS actions in mice. Data derived from a Stx/LPS murine model of HUS indicate that LPS is the primary elicitor of fibrin deposition in kidneys. This pathway requires chemokines and platelets but is not responsible for renal failure. Stx is responsible for renal failure in this murine model in a process that involves nonendothelial renal cell types.

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Figure 3

Anti-inflammatory actions of adenosine in HUS. Data derived from an Stx/LPS murine model of HUS suggest adenosine A2a receptor agonist, i.e., adenosine, effectively blocks the actions of LPS (enhanced by Stx2) at the level of different renal cell types to prevent platelet activation and coagulation.

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Figure 4

Neutrophil-endothelial cell interactions in HUS. In the Stx2/LPS murine model of HUS, analysis of renal gene activation and neutrophil infiltration into kidneys demonstrates a concomitant increase in PMNs and VCAM-1 expression, suggesting a mechanism of PMN-endothelial association. ♦, Neutrophils in the glomeruli; ▪, VCAM-1 in the glomeruli.

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Figure 5

Renal gene activation in the Stx/LPS murine model. Shown are the nine most upregulated genes in the temporal response of mice to either LPS or Stx2. Gene microarrays were employed to analyze kidney gene activation over a 72-h response of C57BL/6 mice to 300 µg/kg of LPS or 100 ng/kg of Stx2.

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Figure 6

Metabolic and catabolic pathway enzymes for Gb synthesis. A part of Gb synthesis pathway is shown. From lactosylceramide (LacCer) to Gb, alpha 1, 4-galactosyltransferase (EC 2.4.1.228) adds a galactose to LacCer to produce Gb. Likewise, UDP-GalNAc: beta 1,3-galactosaminyltransferase (EC 2.4.1.79) works on Gb to make Gb. In the catabolic pathway, beta-hexosaminidase (EC 3.2.1.52) degrades Gb to Gb, and alpha-galactosidase (EC 3.2.1.22) makes LacCer from Gb.

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
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Tables

Generic image for table
TABLE 1

STEC oral administration model with CNS descriptions

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
Generic image for table
TABLE 2

Observed CNS symptoms in animal models

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013
Generic image for table
TABLE 3

Shiga toxin and/or LPS administration model with CNS descriptions

Citation: Obata F, Obrig T. 2015. Role of Shiga/Vero Toxins in Pathogenesis, p 97-130. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0005-2013

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