Characterization of Serotype CD Mosaic Botulinum Neurotoxin in Comparison with Serotype C and A
Author:
Miyashita Shin-Ichiro1ORCID, Karatsu Shura1, Fujiishi Mako1, Huang I Hsun1ORCID, Nagashima Yuki1, Morobishi Tamaki1, Hosoya Keita1, Hata Tsuyoshi1, Dong Min234, Sagane Yoshimasa1
Affiliation:
1. Department of Food, Aroma and Cosmetic Chemistry, Faculty of Bioindustry, Tokyo University of Agriculture, Abashiri 099-2493, Hokkaido, Japan 2. Department of Urology, Boston Children’s Hospital, Boston, MA 02115, USA 3. Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA 4. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
Abstract
Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, cleaves proteins involved in neurotransmitter release, thereby triggering flaccid paralyses, which are responsible for botulism. BoNT is classified into seven serotypes (BoNT/A-G); BoNT/A and BoNT/B are used as medical therapeutics and anti-wrinkle reagents. In this study, we investigated the efficacy of BoNT/CD, a mosaic toxin of BoNT/C and BoNT/D, to assess its potential as a therapeutic alternative for BoNT/A. In a cultured neuron assay, BoNT/CD cleaved syntaxin and SNAP-25 with higher efficacy than BoNT/C and BoNT/A. Intramuscularly administrated BoNT/CD induced dose-dependent muscle paralysis, and the paralysis lasted ~21 days in a mouse digit abduction score assay (BoNT/A-induced paralysis lasted ~30 days). BoNT/C failed to induce local paralysis without systemic toxicity. Multiple alignment analyses of the amino acid sequences of the receptor binding domain (HC) of eight BoNT/CDs and two BoNT/Ds showed sequence clustering in five groups. Comparing BoNT/CD strain 003-9 (BoNT/CD003-9) and strain 6813 (BoNT/CD6813) showed that both BoNT/CDs displayed similar efficacies in cultured neurons, but BoNT/CD003-9 displayed higher efficacy in a mouse model than BoNT/CD6813. These findings suggest that BoNT/CD may be a potential alternative for patients who do not respond to existing BoNT-based therapeutics.
Subject
Health, Toxicology and Mutagenesis,Toxicology
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