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Shiga toxin: intestinal cell receptors and pathophysiology of enterotoxic effects
G T Keusch1, M Jacewicz, M Mobassaleh
1Department of Medicine, New England Medical Center, Boston, Massachusetts 02111.
Abstract:
Shiga toxin is enterotoxic in rabbit small bowel and binds to the microvillus membrane (MVM). The toxin exhibits specificity for glycolipids possessing a terminal gal-alpha 1----4gal disaccharide, including the neutral glycolipid Gb3 in MVM. Gb3, which is developmentally regulated in the rabbit small bowel, is present in very low concentration until the animals reach day 16 of life. In older animals an increase in Gb3 content is paralleled by an increase in the ability of MVM to bind toxin, which also correlates with the fluid secretion response. Shiga toxin selectively binds to villus cells, which contain Gb3, and not to crypt cells, which do not express Gb3. Targeting of the villus cell by the toxin is consistent with physiologic studies that demonstrate inhibition of villus cell Na+ absorptive pathways, with no effect on crypt cell Cl- secretory mechanisms. These effects are sufficient to account for the enterotoxicity of Shiga toxin in the rabbit model.
Insights
Shiga toxin targets rabbit small intestine villus cells by binding to the glycolipid Gb3. This interaction inhibits sodium absorption, causing fluid secretion and enterotoxicity in developing rabbits.
Area of Science:
- Microbiology
- Gastroenterology
- Cell Biology
Background:
- Shiga toxin causes enteritis by binding to specific glycolipids on the intestinal microvillus membrane (MVM).
- The neutral glycolipid Gb3, with a terminal gal-alpha 1----4gal disaccharide, is a key binding site for Shiga toxin.
- Gb3 expression in the rabbit small bowel is developmentally regulated.
Purpose of the Study:
- To investigate the role of Gb3 in Shiga toxin enterotoxicity in the rabbit small bowel.
- To determine the cellular localization of Shiga toxin binding and its correlation with Gb3 expression and physiological effects.
Main Methods:
- Analysis of Gb3 concentration in rabbit MVM at different developmental stages.
- Assessment of Shiga toxin binding to MVM and its correlation with fluid secretion.
- Cellular localization studies of Shiga toxin binding in relation to villus and crypt cells.
Main Results:
- Gb3 concentration in rabbit small bowel MVM increases significantly after day 16 of life.
- Increased Gb3 levels correlate with enhanced Shiga toxin binding and fluid secretion.
- Shiga toxin selectively binds to villus cells expressing Gb3, sparing Gb3-negative crypt cells.
Conclusions:
- Shiga toxin's enterotoxicity in rabbits is mediated by Gb3 binding to villus cells.
- The developmental regulation of Gb3 influences the susceptibility to Shiga toxin.
- Inhibition of villus cell sodium absorption by Shiga toxin explains its enterotoxic effects.