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Modulation of enterotoxin binding and function in vitro and in vivo
S T Donta1, P Damiano-Burbach, N J Poindexter
1Department of Medicine, University of Connecticut, Newington.
Abstract:
The use of the nontoxic B subunits of cholera and Escherichia coli enterotoxins in vitro and in vivo led to a decrease in toxin binding to target cells and a decrease in toxin-induced effects (i.e., morphological effects, adenylate cyclase activation, and fluid secretion). The reduction in toxin binding involves a process of down-regulation of cellular receptors for the toxin and not toxin occupancy of receptors. The extent of inhibition was dependent on the amount of B subunit used and on the duration of time after its use. Thus, in vivo exposure to a single bolus of B subunit was sufficient to block toxin binding and activity for up to 18 h. Because the B subunit binds extensively to the esophagus and the stomach, peroral administration will require a preparation that allows the subunit to reach the small bowel in a protected form. Our data provide a rationale for using B subunit therapy for short-term protection against the effects of enterotoxins, before the development of an immune response.
Insights
Nontoxic B subunits of cholera and E. coli enterotoxins block toxin binding and effects by down-regulating cellular receptors. This offers short-term protection against enterotoxins, with administration requiring protection for small bowel delivery.
Area of Science:
- Microbiology
- Toxicology
- Pharmacology
Background:
- Cholera and E. coli enterotoxins cause significant gastrointestinal illness.
- Enterotoxin B subunits are nontoxic and can interfere with toxin binding.
Purpose of the Study:
- To investigate the efficacy of nontoxic enterotoxin B subunits in preventing toxin binding and effects.
- To elucidate the mechanism of B subunit-mediated inhibition of enterotoxin activity.
Main Methods:
- In vitro and in vivo experiments using B subunits of cholera and E. coli enterotoxins.
- Assessing toxin binding, receptor down-regulation, and toxin-induced cellular effects (morphological changes, adenylate cyclase activation, fluid secretion).
- Evaluating the duration and dose-dependency of B subunit inhibition.
Main Results:
- B subunit administration significantly decreased enterotoxin binding and subsequent effects.
- Inhibition resulted from cellular receptor down-regulation, not receptor occupancy.
- A single in vivo dose provided protection for up to 18 hours.
- Peroral administration requires protection to bypass the esophagus and stomach.
Conclusions:
- Nontoxic B subunits can be utilized for short-term therapeutic protection against enterotoxins.
- Understanding B subunit-receptor interactions is crucial for developing effective delivery strategies.
- B subunit therapy presents a potential strategy before an immune response develops.