针对 B 型肉毒杆菌神经毒素的人类单克隆抗体的中和机制。

IF 1.9 4区 医学 Q4 IMMUNOLOGY Microbiology and Immunology Pub Date : 2024-09-06 DOI:10.1111/1348-0421.13171
Takuhiro Matsumura, Mayu Kitamura, Sho Amatsu, Aki Yamaguchi, Nobuhide Kobayashi, Masahiro Yutani, Yukako Fujinaga
{"title":"针对 B 型肉毒杆菌神经毒素的人类单克隆抗体的中和机制。","authors":"Takuhiro Matsumura,&nbsp;Mayu Kitamura,&nbsp;Sho Amatsu,&nbsp;Aki Yamaguchi,&nbsp;Nobuhide Kobayashi,&nbsp;Masahiro Yutani,&nbsp;Yukako Fujinaga","doi":"10.1111/1348-0421.13171","DOIUrl":null,"url":null,"abstract":"<p>Botulism is a deadly neuroparalytic condition caused by the botulinum neurotoxin (BoNT) produced by <i>Clostridium botulinum</i> and related species. Toxin-neutralizing antibodies are the most effective treatments for BoNT intoxication. We generated human monoclonal antibodies neutralizing type B botulinum neurotoxin (BoNT/B), designated M2 and M4. The combination of these antibodies exhibited a strong neutralizing effect against BoNT/B toxicity. In this study, we analyzed the mechanisms of action of these antibodies in vitro. M4 binds to the C-terminus of the heavy chain (the receptor-binding domain) and inhibits BoNT/B binding to neuronal PC12 cells. Although M2 recognized the light (L) chain (the metalloprotease domain), it did not inhibit substrate (VAMP2) cleavage in the cleavage assay. M2 increased the surface localization of BoNT/B in PC12 cells at a later time point, suggesting that M2 inhibits the translocation of the L chain from synaptic vesicles to the cytosol. These results indicate that M2 and M4 inhibit the different processes of BoNT/B individually and that multistep inhibition is important for the synergistic effect of the combination of monoclonal antibodies. Our findings may facilitate the development of effective therapeutic antibodies against BoNTs.</p>","PeriodicalId":18679,"journal":{"name":"Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Neutralization mechanism of human monoclonal antibodies against type B botulinum neurotoxin\",\"authors\":\"Takuhiro Matsumura,&nbsp;Mayu Kitamura,&nbsp;Sho Amatsu,&nbsp;Aki Yamaguchi,&nbsp;Nobuhide Kobayashi,&nbsp;Masahiro Yutani,&nbsp;Yukako Fujinaga\",\"doi\":\"10.1111/1348-0421.13171\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Botulism is a deadly neuroparalytic condition caused by the botulinum neurotoxin (BoNT) produced by <i>Clostridium botulinum</i> and related species. Toxin-neutralizing antibodies are the most effective treatments for BoNT intoxication. We generated human monoclonal antibodies neutralizing type B botulinum neurotoxin (BoNT/B), designated M2 and M4. The combination of these antibodies exhibited a strong neutralizing effect against BoNT/B toxicity. In this study, we analyzed the mechanisms of action of these antibodies in vitro. M4 binds to the C-terminus of the heavy chain (the receptor-binding domain) and inhibits BoNT/B binding to neuronal PC12 cells. Although M2 recognized the light (L) chain (the metalloprotease domain), it did not inhibit substrate (VAMP2) cleavage in the cleavage assay. M2 increased the surface localization of BoNT/B in PC12 cells at a later time point, suggesting that M2 inhibits the translocation of the L chain from synaptic vesicles to the cytosol. These results indicate that M2 and M4 inhibit the different processes of BoNT/B individually and that multistep inhibition is important for the synergistic effect of the combination of monoclonal antibodies. Our findings may facilitate the development of effective therapeutic antibodies against BoNTs.</p>\",\"PeriodicalId\":18679,\"journal\":{\"name\":\"Microbiology and Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2024-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Microbiology and Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/1348-0421.13171\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Microbiology and Immunology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1348-0421.13171","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

肉毒中毒是一种致命的神经麻痹病症,由肉毒梭状芽孢杆菌及相关菌种产生的肉毒神经毒素(BoNT)引起。毒素中和抗体是治疗 BoNT 中毒最有效的方法。我们生成了中和 B 型肉毒杆菌神经毒素(BoNT/B)的人类单克隆抗体,命名为 M2 和 M4。这些抗体的组合对 BoNT/B 的毒性有很强的中和作用。在这项研究中,我们分析了这些抗体在体外的作用机制。M4 与重链的 C 端(受体结合域)结合,抑制 BoNT/B 与神经元 PC12 细胞的结合。虽然 M2 能识别轻(L)链(金属蛋白酶结构域),但在裂解试验中并不能抑制底物(VAMP2)的裂解。在较晚的时间点,M2 增加了 BoNT/B 在 PC12 细胞中的表面定位,这表明 M2 抑制了 L 链从突触小泡向细胞膜的转运。这些结果表明,M2和M4可分别抑制BoNT/B的不同过程,而多步骤抑制对单克隆抗体组合的协同效应非常重要。我们的研究结果可能有助于开发针对BoNTs的有效治疗抗体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Neutralization mechanism of human monoclonal antibodies against type B botulinum neurotoxin

Botulism is a deadly neuroparalytic condition caused by the botulinum neurotoxin (BoNT) produced by Clostridium botulinum and related species. Toxin-neutralizing antibodies are the most effective treatments for BoNT intoxication. We generated human monoclonal antibodies neutralizing type B botulinum neurotoxin (BoNT/B), designated M2 and M4. The combination of these antibodies exhibited a strong neutralizing effect against BoNT/B toxicity. In this study, we analyzed the mechanisms of action of these antibodies in vitro. M4 binds to the C-terminus of the heavy chain (the receptor-binding domain) and inhibits BoNT/B binding to neuronal PC12 cells. Although M2 recognized the light (L) chain (the metalloprotease domain), it did not inhibit substrate (VAMP2) cleavage in the cleavage assay. M2 increased the surface localization of BoNT/B in PC12 cells at a later time point, suggesting that M2 inhibits the translocation of the L chain from synaptic vesicles to the cytosol. These results indicate that M2 and M4 inhibit the different processes of BoNT/B individually and that multistep inhibition is important for the synergistic effect of the combination of monoclonal antibodies. Our findings may facilitate the development of effective therapeutic antibodies against BoNTs.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Microbiology and Immunology
Microbiology and Immunology 医学-免疫学
CiteScore
5.20
自引率
3.80%
发文量
78
审稿时长
1 months
期刊介绍: Microbiology and Immunology is published in association with Japanese Society for Bacteriology, Japanese Society for Virology, and Japanese Society for Host Defense Research. It is peer-reviewed publication that provides insight into the study of microbes and the host immune, biological and physiological responses. Fields covered by Microbiology and Immunology include:Bacteriology|Virology|Immunology|pathogenic infections in human, animals and plants|pathogenicity and virulence factors such as microbial toxins and cell-surface components|factors involved in host defense, inflammation, development of vaccines|antimicrobial agents and drug resistance of microbes|genomics and proteomics.
期刊最新文献
Issue Information – Cover A single amino acid substitution in the Borna disease virus glycoprotein enhances the infectivity titer of vesicular stomatitis virus pseudotyped virus by altering membrane fusion activity. Structure-based virtual screening and drug repurposing studies indicate potential inhibitors of bovine papillomavirus E6 oncoprotein. Downregulation of CD86 in HCMV-infected THP-1 cells. Issue Information – Cover
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1