The neuroparalytic disease botulism, caused by botulinum toxin (BoNT), requires specific receptor-mediated epithelial cell transport and specific interactions with neuronal receptors to cause paralysis. Neuronal receptors for BoNT have been identified, but little is known about the epithelial receptors for BoNT. Elias et al. addressed differentiation of these anatomically distinct BoNT receptor types by focusing on the initial polysialoganglioside binding of BoNT to epithelial and neuronal receptors. Using mutants of the carboxyl-terminal half of the heavy chain (HC50), the site known to interact with polysialogangliosides, they were able to identify a dimutant form of HC50 that bound only to epithelial and not neuronal BoNT receptors, providing the first evidence that the epithelial and neuronal BoNT receptors are not identical. The ability of the dimutant HC50 to undergo transepithelial transport was also demonstrated in vivo. The dimutant HC50 was immunogenic and afforded protection against a substantial challenge dose of BoNT. Alterations in the HC50 domain that abolish neuronal binding (potentially non-neurotropic) but that do not abolish epithelial transport or immunogenicity represent a substantial advance in vaccine development for botulism.
See article at J Pharmacol Exp Ther 2011, 336:605–612.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics