Abstract
The botulinum neurotoxin (BoNT) causes muscle paralysis and is the most potent toxin in nature. BoNT is associated with a complex of auxiliary “Non-Toxic” proteins, which constitute a large-sized toxin complex (L-TC). However, here we report that the “Non-Toxic” complex of serotype D botulinum L-TC, when administered to rats, exerts in-vivo toxicity on small-intestinal villi. Moreover, Serotype C and D of the “Non-Toxic” complex, but not BoNT, induced vacuole-formation in a rat intestinal epithelial cell line (IEC-6), resulting in cell death. Our results suggest that the vacuole was formed in a manner distinct from the mechanism by which Helicobacter pylori vacuolating toxin (VacA) and Vibrio cholerae haemolysin induce vacuolation. We therefore hypothesise that the serotype C and D botulinum toxin complex is a functional hybrid of the neurotoxin and vacuolating toxin (VT) which arose from horizontal gene transfer from an ancestral BoNT-producing bacterium to a hypothetical VT-producing bacterium.
Highlights
The botulinum neurotoxin (BoNT), the most potent toxin in nature, is categorised into seven distinct serotypes, A through G
The large-sized toxin complex (L-TC), BoNT, and “Non-Toxic” protein complex preparations used in this investigation were purified to a high degree from a culture of C. botulinum serotype C strain Stockholm (C-St) and D strain 4947 (D-4947) (Supplementary Fig. 1)
Leakage of cellular lactate dehydrogenase (LDH), increased upon the addition of the L-TC and “Non-Toxic” complex (Fig. 1c); while BoNT did not induce a decrease in the number of viable cell or increase LDH leakage (Fig. 1b,c, respectively)
Summary
The botulinum neurotoxin (BoNT), the most potent toxin in nature, is categorised into seven distinct serotypes, A through G. While the BoNT protein in complex with the NTNHA protein exhibits notable tolerance to these digestive conditions[4], the BoNT protein when it is free of the non-toxic proteins is degraded into small fragments in the stomach and intestine. The NTNHA protein plays a role in protecting BoNT against the digestive conditions in the gastrointestinal tracts of animals and humans. It has been shown that the serotype A BoNT complex disrupts E-cadherin adhesion, thereby disrupting interactions between epithelial cells[7]. This process may facilitate the trans-epithelial transport of the toxin complex. We demonstrate that the “Non-Toxic” complex of serotype D botulinum L-TC, when administered to rats, exerts in-vivo toxicity on small-intestinal villi
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