Abstract
To cause food-borne botulism, botulinum neurotoxin (BoNT) in the gastrointestinal lumen must traverse the intestinal epithelial barrier. However, the mechanism by which BoNT crosses the intestinal epithelial barrier remains unclear. BoNTs are produced along with one or more non-toxic components, with which they form progenitor toxin complexes (PTCs). Here we show that serotype A1 L-PTC, which has high oral toxicity and makes the predominant contribution to causing illness, breaches the intestinal epithelial barrier from microfold (M) cells via an interaction between haemagglutinin (HA), one of the non-toxic components, and glycoprotein 2 (GP2). HA strongly binds to GP2 expressed on M cells, which do not have thick mucus layers. Susceptibility to orally administered L-PTC is dramatically reduced in M-cell-depleted mice and GP2-deficient (Gp2−/−) mice. Our finding provides the basis for the development of novel antitoxin therapeutics and delivery systems for oral biologics.
Highlights
To cause food-borne botulism, botulinum neurotoxin (BoNT) in the gastrointestinal lumen must traverse the intestinal epithelial barrier
There was no significant difference among the toxicities of the intraperitoneally administered toxins. These results indicate that L-progenitor toxin complexes (PTCs) makes the predominant contribution to the onset of food-borne botulism
After a 3-h incubation, L-PTC was located on the basolateral side of the follicleassociated epithelium (FAE) and in CD11c þ dendritic cells (CD11c þ DCs), which are located in the sub-epithelial dome (Supplementary Fig. 1a)
Summary
To cause food-borne botulism, botulinum neurotoxin (BoNT) in the gastrointestinal lumen must traverse the intestinal epithelial barrier. BoNTs are produced along with one or more non-toxic components, with which they form progenitor toxin complexes (PTCs). We show that serotype A1 L-PTC, which has high oral toxicity and makes the predominant contribution to causing illness, breaches the intestinal epithelial barrier from microfold (M) cells via an interaction between haemagglutinin (HA), one of the non-toxic components, and glycoprotein 2 (GP2). At least three mechanisms possibly involved in this phenomenon have been reported: protection of BoNT by NTNHA and HA against degradation in the gastrointestinal tract[2,11]; promotion of binding to intestinal epithelial cells through the carbohydrate-binding activity of HA12 and disruption of the epithelial barrier via an interaction between HA and E-cadherin[13,14,15,16]. Our data reveal that to exert its toxic effects, type A1 L-PTC invades the intestinal epithelium through M cells via HA–GP2 interaction
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