肉毒梭菌及其毒素分型方法概述

杨英超 张华捷 马霄

杨英超, 张华捷, 马霄. 肉毒梭菌及其毒素分型方法概述[J]. 疾病监测. doi: 10.3784/jbjc.202011300401
引用本文: 杨英超, 张华捷, 马霄. 肉毒梭菌及其毒素分型方法概述[J]. 疾病监测. doi: 10.3784/jbjc.202011300401
Yang Yingchao, Zhang Huajie, Ma Xiao. Review on Clostridium botulinum and its toxin typing methods[J]. Disease Surveillance. doi: 10.3784/jbjc.202011300401
Citation: Yang Yingchao, Zhang Huajie, Ma Xiao. Review on Clostridium botulinum and its toxin typing methods[J]. Disease Surveillance. doi: 10.3784/jbjc.202011300401

肉毒梭菌及其毒素分型方法概述

doi: 10.3784/jbjc.202011300401
基金项目: 国家重大新药创制(No. 2018ZX09738–005)
详细信息
    作者简介:

    杨英超,男,博士研究生,主要从事生物毒素和疟疾等生物制品检定及研究,Email:yangyc@nifdc.org.cn

    张华捷,男,博士研究生,主要从事毒素和微生态制剂等生物制品检定及研究,Email:zhanghj@nifdc.org.cn

    通讯作者:

    马霄,Email:maxiao421@sina.cn

  • 作者1和作者2同为第一作者
  • 中图分类号: R211; R378.8+3

Review on Clostridium botulinum and its toxin typing methods

  • 摘要: 自1897年Ermengem分离并报道了可形成孢子的肉毒梭菌导致人类中毒以来,研究人员通过血清中和方法发现自然界中存在7种不同型别的肉毒梭菌。 随后,再次应用血清学方法又发现了可产生双价毒素Ab、Ba、AB、Af和Bf等肉毒梭菌。 随着基因测序技术的逐渐成熟和完善,通过提取肉毒梭菌基因进行全基因组测序,不仅可识别不同血清型肉毒毒素的基因组成,也可开展核酸或蛋白质分子水平的分型研究。 相比血清中和分型方法,这些新涌现的分型技术和方法不仅可解开血清学分类中遇到的难题,更可快速准确的鉴别肉毒梭菌导致的食物或药物中毒,并追踪源头及应用相应药物治疗。 此外,不同分型方法对于肉毒梭菌菌种鉴定和使用,新型毒素的研发都提供了新的工具和思路。
    1)  作者1和作者2同为第一作者
  • 图  1  肉毒梭菌神经毒素结构和分子靶标5

    注:A. 原始单链毒素被内源性蛋白酶切割为具有活性的双链,其中重链负责结合和内吞,轻链具有锌依赖内蛋白酶活性。B. 携带乙酰胆碱神经递质(Ach)的突触小泡与神经元质膜融合,通过突触连接传递神经冲动。这一融合需要形成SNARE复合物,即突触小泡上的VAMP-2与神经元膜上的Syntaxin和SNAP-25之间的相互作用。肉毒杆菌神经毒素(BoNTs)可在上述3种蛋白质的特异位点切割肽键。任何一种蛋白质被切割后都能阻止囊泡对接及神经冲动传递

    Figure  1.  Botulinum neurotoxin structure and molecular targets5

    图  2  BoNTs的基因簇结构3334

    Figure  2.  The two different toxin gene clusters within botulinum neurotoxin-producing strains3334

    图  3  BoNT及其毒素亚型的树状图3334

    Figure  3.  Dendrogram of BoNT and toxin subtypes3334

    图  4  使用UPGMA分析绘制46株肉毒杆菌经Sma酶切PFGE树状图48, 54

    Figure  4.  Dendrogram of 46 C. botulinum strains based on PFGE Sma Ⅰ profiles48, 54

    图  5  A~G型毒素经MALDI-TOF MS多重检测5

    Figure  5.  Multiplexed detection of BoNT-A–G by MALDI-TOF MS5

    表  1  MLST新序列型及新等位基因序列33, 48

    Table  1.   New MLST sequence types and new allele sequences33, 48

    序列型 等位基因
    recA rpoB oppB hsp60 aceK mdh aroE
    25 7 8 10 8 6 8 10
    26 7 8 9 8 7 8 9
    27 8 8 9 8 7 8 10
    28 7 10 12 8 14 11 14
    下载: 导出CSV

    表  2  VNTR引物序列及特征56

    Table  2.   VNTR primer sequences and characteristics56

    VNTR Primer sequence Genomic locationa Sequence of repeat unit Repeat unit size (bp) Diversity index
    21F  TGCATTCAGGACATAACTCTT 1021136~1021489  TTCTTATC 8 0.8959
    21R  TATGTTTCCGATAAGTGTTCAT 1966109~1966453  ATTTTAATTAAAAGGAG 17 0.2998
    24F  TGGAATGAGTGGAAGAAGTG
    24R  ATGCTTGCCATATTGAAATC
    25F  TAACAGTCGTAGGGTGTTAGC 2468172~2468657  AGAATTTA 8 0.9328
    25R  TGGAACTCTATGTGCTGAAAG
      注:a. 在肉毒杆菌Alaska E43(NC_010723.1)基因的位置
    下载: 导出CSV

    表  3  Endopep-MS试验多肽序列5

    Table  3.   Peptide sequences for the BoNT Endopep-MS Assay5

    分组      Botulinum Neurotoxin Specific Peptide SubstratesMaits
    1. BoNT-A.-C Substrate Biotin-KGSNRTRIDEANQaRcATRMLGGK-Biotin2910.5
     BoNT-A NTP Biotin-KGSNRTRIDEANQa1713.8
     BoNT-A CTP aRATRMLGGK-Biotin1214.6
     BoNT-C NTP Biotin-KGSNRTRIDEANQRc1869.9
     BoNT-C CTP cATRMLGGK-Biotin1058.5
    2. BoNT-E Substrate IIGNLRHMALDMGNEIDTQNRQIDReIMEKAD3609.8
     BoNT-E NTP IIGNLRHMALDMGNEIDTQNRQIDRe2922.5
     BoNT-E CTP eIMEKAD 705.3
    3. BoNT-B.-G Substrate LSELDDRADALQAGASQbFETSAgAKLKRKYWWKNLK4037.1
     BoNT-B NTP LSELDDRADALQAGASQb1758.8
     BoNT-B CTP bFETSAAKLKRKYWWKNLK2296.3
     BoNT-G NTP LSELDDRADALQAGASQFETSAg2294.1
     BoNT-G CTP gAKLKRKYWWKNLK1761.1
    4. BoNT-D.-F Substrate AQVDEVVDIMRVNVDKVLERDQfKdLSELDDRADALQAGAS4310.2
     BoNT-D NTP AQVDEVVDIMRVNVDKVLERDQKd2697.4
     BoNT-D CTP dLSELDDRADALQAGAS1630.8
     BoNT-F NTP AQVDEVVDIMRVNVDKVLERDQf2569.3
     BoNT-F CTP fKLSELDDRADALQAGAS1758.9
    5. Internal Standard LRTAQADITNSK-(ε)Biotin1542.8
    6. BoNT-A Substrate Biotin-KGSNRTRIDEGNQaRATRXLGGK-Biotin(X = norleucine)2880.3
     BoNT-A NTP Biotin-KGSNRTRIDEGNQa1699.8
     BoNT-A CTP aRATRXLGGK-Biotin1196.7
      注:字母上标代表不同毒素型别的切割位点。A、C和E型毒素作用底物序列来自人SNAP-25蛋白(P60880);B、D和F型毒素作用底物序列来自人VAMP-2(NP_055047)
    下载: 导出CSV
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  • 收稿日期:  2020-11-30
  • 网络出版日期:  2021-05-13

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