A novel function of botulinum toxin-associated proteins: HA proteins disrupt intestinal epithelial barrier to increase toxin absorption.

Food-borne botulinum neurotoxin (BoNT) in the gastrointestinal lumen must cross an epithelial barrier to reach peripheral nerves to mediate its toxicity. The detailed mechanism by which BoNT traverses this barrier remains unclear. We found that hemagglutinin (HA) proteins of type B BoNT complex play an important role in the intestinal absorption of BoNT, disrupting the paracellular barrier of intestinal epithelium, which facilitates transepithelial delivery of BoNT both in vitro and in vivo (Matsumura, T., et al., 2008. Cell. Microbiol. 10, 355-364). We also found that type A HA proteins have a similar disrupting activity with a greater potency than type B HA proteins in the human intestinal epithelial cell lines Caco-2 and T84. In contrast, type C HA proteins in the toxin complex (up to 300 nM) have no detectable effect on the paracellular barrier in these human cell lines. These results may indicate that types A and B HA contribute to develop the food-borne human botulism by facilitating the intestinal transepithelial delivery of BoNTs.