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Intestinal kinetics and dynamics of Escherichia coli heat-stabile enterotoxin in suckling mice
S A Waldman1, K Phillips, S J Parkinson
1Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Abstract:
The heat-stabile enterotoxin produced by Escherichia coli (ST) induces diarrhea by binding to receptors on intestinal cells, activating guanylyl cyclase, and increasing cyclic GMP. High- and low-affinity receptors for this toxin have been identified previously. ST induces intestinal secretion in suckling mice in picomole doses, suggesting a role for high-affinity receptors in this process. The present studies examine the relative roles of high- and low-affinity receptors in this process. The time course of changes in free ST concentrations in suckling mouse intestine was determined after intragastric inoculation. Also, binding characteristics of high- and low-affinity receptors and their coupling to guanylyl cyclase were defined in intestinal membranes from suckling mice. Intestinal concentrations of toxin and receptor binding characteristics empirically determined were used in a dynamic model correlating fractional occupancy of high- and low-affinity receptors with intestinal secretion to estimate their relative contributions to ST-induced diarrhea.
Insights
Escherichia coli heat-stabile enterotoxin (ST) causes diarrhea by activating intestinal cells. This study quantifies the roles of high- and low-affinity ST receptors in mediating this secretory response in suckling mice.
Area of Science:
- Microbiology
- Gastroenterology
- Molecular Biology
Background:
- Escherichia coli heat-stabile enterotoxin (ST) is a key virulence factor causing diarrhea.
- ST functions by binding to intestinal receptors, activating guanylyl cyclase, and increasing cyclic GMP levels.
- Both high- and low-affinity ST receptors have been previously identified.
Purpose of the Study:
- To investigate the relative contributions of high- and low-affinity receptors to ST-induced intestinal secretion.
- To correlate receptor occupancy with the physiological response in a suckling mouse model.
Main Methods:
- Determined the time course of free ST concentrations in suckling mouse intestine post-inoculation.
- Characterized binding properties of high- and low-affinity receptors and their guanylyl cyclase coupling in intestinal membranes.
- Developed a dynamic model using empirical toxin and receptor data to estimate receptor roles.
Main Results:
- Quantified ST concentrations and receptor binding kinetics in vivo and in vitro.
- The dynamic model provided estimates for the relative contributions of high- and low-affinity receptors to ST-induced secretion.
- Established a correlation between fractional receptor occupancy and the magnitude of intestinal secretion.
Conclusions:
- Both high- and low-affinity receptors play significant roles in mediating ST-induced diarrhea.
- Understanding receptor dynamics is crucial for elucidating the pathogenesis of ST-mediated intestinal secretion.
- This study provides a quantitative framework for assessing the impact of receptor interactions on toxin-induced physiological responses.