A novel function of botulinum toxin-associated proteins: The HA component disrupts intestinal epithelial intercellular junctions to increase toxin absorption

Abstract

Food-borne BoNTs in the gastrointestinal lumen must cross an epithelial barrier to reach nerve terminals to mediate toxicity. The detailed mechanism by which BoNTs traverse this barrier and enter the circulation remains unclear. Type B BoNT forms two distinct complexes, 12S and 16S, through associations with different sets of non-toxic proteins (non-toxic neurotoxin-associated proteins, NAPs). The 12S toxin is composed of BoNT and a non-toxic protein lacking hemagglutinin (HA) activity, and it is designated non-toxic non-HA (NTNH). The 16S toxin consists of BoNT, NTNH and HA proteins. NAPs are known to markedly increase the oral toxicity of BoNT. We found that type B HA proteins play an important role in the intestinal absorption of BoNT by disrupting the paracellular barrier of the intestinal epithelium. This action facilitates and enhances the transepithelial delivery of BoNT both in vitro and in vivo (T. Matsumura, et al., 2008. Cell. Microbiol. 10, 355–364). Recent experiments showed that type A HA proteins have a similar disrupting activity with greater potency as compared to type B HA proteins in human intestinal epithelial cell lines, Caco-2 and T84. These and other results will be presented and discussed.