Unique biological activity of botulinum D/C mosaic neurotoxin in murine species.

Abstract

Clostridium botulinum types C and D cause animal botulism by the production of serotype-specific or mosaic botulinum neurotoxin (BoNT). The D/C mosaic BoNT (BoNT/DC), which is produced by the isolate from bovine botulism in Japan, exhibits the highest toxicity to mice among all BoNTs. In contrast, rats appeared to be very resistant to BoNT/DC in type C and D BoNTs and their mosaic BoNTs. We attempted to characterize the enzymatic and receptor-binding activities of BoNT/DC by comparison with those of type C and D BoNTs (BoNT/C and BoNT/D). BoNT/DC and D showed similar toxic effects on cerebellar granule cells (CGCs) derived from the mouse, but the former showed less toxicity to rat CGCs. In recombinant murine-derived vesicle-associated membrane protein (VAMP), the enzymatic activities of both BoNTs to rat isoform 1 VAMP (VAMP1) were lower than those to the other VAMP homologues. We then examined the physiological significance of gangliosides as the binding components for types C and D, and mosaic BoNTs. BoNT/DC and C were found to cleave an intracellular substrate of PC12 cells upon the exogenous addition of GM1a and GT1b gangliosides, respectively, suggesting that each BoNT recognizes a different ganglioside moiety. The effect of BoNT/DC on glutamate release from CGCs was prevented by cholera toxin B-subunit (CTB) but not by a site-directed mutant of CTB that did not bind to GM1a. Bovine adrenal chromaffin cells appeared to be more sensitive to BoNT/DC than to BoNT/C and D. These results suggest that a unique mechanism of receptor binding of BoNT/DC may differentially regulate its biological activities in animals.

• Authors: Keiji Nakamura, Tomoko Kohda, Yuto Shibata, Kentaro Tsukamoto, Hideyuki Arimitsu, Mitsunori Hayashi, Masafumi Mukamoto, Nobuyuki Sasakawa, Shunji Kozaki
• Journal: Infection and immunity (Infect Immun) Vol. 80 Issue 8 Pg. 2886-93 (Aug 2012) ISSN: 1098-5522 [Electronic] United States
• PMID: 22665374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gangliosides
• Neurotoxins
• Recombinant Proteins
• Botulinum Toxins

Topics

• Adrenal Glands (cytology)
• Animals
• Botulinum Toxins (classification, metabolism, toxicity)
• Cattle
• Cerebellum (cytology)
• Chromaffin Cells (drug effects)
• Clostridium botulinum (metabolism)
• Female
• Gangliosides (metabolism)
• Mice
• Neurotoxins (classification, metabolism, toxicity)
• PC12 Cells
• Protein Binding
• Rats
• Recombinant Proteins
• Species Specificity