Jingrong Wang, Jiansheng Lu, Bolin Li, Xiaoyu Liu, Rong Wang, Peng Du, Shuo Yu, Zhixin Yang, Yunzhou Yu
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引用次数: 0
摘要
肉毒杆菌神经毒素(BoNTs),包括血清型 A 和 E,是已知可导致人类中毒的强效生物毒素。除了完整 BoNT 分子中的关键保护性抗原--受体结合结构域(Hc 结构域)外,BoNTs 还含有另一个重要的保护性抗原--轻链-转座结构域(L-HN 结构域)。利用这些关键的保护性抗原,我们从基因上设计了一系列灭活的嵌合分子,其中包含 BoNT/A 和 E 的 L-HN 和 Hc 结构域。实验结果表明,候选药物 mEL-HN-mAHc 利用失活的蛋白酶 LCHN/E 和变异的神经节苷脂结合位点 Hc/A(mE-mA),在小鼠模型中同时对 BoNT/A 和 E 产生强大的免疫保护作用,只需较低的免疫剂量和最低限度的免疫接种。此外,mE-mA 对豚鼠和新西兰白兔的 BoNT/A 和 E 具有很高的保护效力,从而导致中和抗体滴度升高。此外,与甲醛灭活的类毒素相比,mE-mA 被证明是一种更稳定、更安全的疫苗。我们的数据强调了基因工程改造的 mE-mA 是一种高效的二价疫苗,可预防 BoNT/A 和 E,为开发多价生物毒素疫苗铺平了道路。
New Engineered-Chimeric Botulinum Neurotoxin Mutant Acts as an Effective Bivalent Vaccine Against Botulinum Neurotoxin Serotype A and E.
Botulinum neurotoxins (BoNTs), including serotypes A and E, are potent biotoxins known to cause human poisoning. In addition to the critical protective antigen found in the full BoNT molecule, the receptor binding domain (Hc domain), BoNTs also harbour another essential protective antigen-the light chain-translocation domain (L-HN domain). Leveraging these pivotal protective antigens, we genetically engineered a series of inactivated chimeric molecules incorporating L-HN and Hc domains of BoNT/A and E. The structure of these chimeric molecules, mirror BoNT/A and E, but are devoid of enzyme activity. Experimental findings demonstrated that a lead candidate mEL-HN-mAHc harnessing the inactivated protease LCHN/E with the mutated gangliosides binding site Hc/A (mE-mA) elicited robust immune protection against BoNT/A and E simultaneously in a mouse model, requiring low immune dosages and minimal immunisations. Moreover, mE-mA exhibited high protective efficacy against BoNT/A and E in guinea pigs and New Zealand white rabbits, resulting in elevated neutralising antibody titres. Furthermore, mE-mA proved to be a more stable and safer vaccine compared to formaldehyde-inactivated toxoid. Our data underscore the genetically engineered mE-mA as a highly effective bivalent vaccine against BoNT/A and E, paving the way for the development of polyvalent vaccines against biotoxins.
期刊介绍:
Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers.
Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology.
The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.