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Sci Transl Med:高福院士揭示寨卡病毒治疗性抗体的机制

2017-02-10 MedSci MedSci原创

中科院微生物研究所严景华研究员与高福院士近期合作揭示高效、特异性人源寨卡病毒(zika virus, ZIKV)治疗性抗体及其机制。研发寨卡病毒治疗性抗体方面取得重要进展,率先找到高效、特异性人源寨卡病毒(zika virus, ZIKV)治疗性抗体及其机制,该抗体在小鼠模型上能有效治疗ZIKV感染,有望成为治疗其感染的候选药物。随着研究的深入,ZIKV的危害逐渐被揭示,从最初的发烧、皮疹等轻

中科院微生物研究所严景华研究员与高福院士近期合作揭示高效、特异性人源寨卡病毒(zika virus, ZIKV)治疗性抗体及其机制。

研发寨卡病毒治疗性抗体方面取得重要进展,率先找到高效、特异性人源寨卡病毒(zika virus, ZIKV)治疗性抗体及其机制,该抗体在小鼠模型上能有效治疗ZIKV感染,有望成为治疗其感染的候选药物。

随着研究的深入,ZIKV的危害逐渐被揭示,从最初的发烧、皮疹等轻微症状,到引起新生儿小头症和格林-巴利综合征等神经系统疾病。最近高福院士团队与Michael Diamond教授团队独立研究均揭示,ZIKV在小鼠模型中引起睾丸损伤并最终导致雄性不育。截至目前还没有ZIKV疫苗及药物上市。

ZIKV表面含有E蛋白(Envelope),含有三个不同的结构域(DI, DII和DIII)是负责受体识别与膜融合的重要蛋白,含有产生中和抗体的重要表位。研究团队从一例南美输入病例入手,采集其康复后的血液并分离PBMCs,然后以ZIKV E蛋白为诱饵从PBMCs中分选到33个结合E蛋白的记忆性B细胞,并且鉴定出其中14个B细胞的抗体序列。表达、纯化这些抗体后,进行一系列的功能验证。首先,ELISA、SPR实验证明有13株抗体结合E蛋白,亲和力相差较大 (KD=10-6~10-11M);竞争实验表明13株抗体结合在E蛋白的至少5个不同表位。其次,细胞水平的体外中和实验表明,结合其中3个表位的抗体具有高中和活性(IC50=0.17~1.87 μg/ml);动物水平(小鼠感染模型)的体内功能检测发现三个不同表位的高中和活性抗体(Z20, Z3L1和Z23)分别可以完全保护小鼠。

最后,利用结构生物学手段,阐明三株保护性抗体与E蛋白的结合模式并揭示其作用机制。其中,Z20同时结合E蛋白二聚体中相邻E蛋白的DII,Z3L1主要结合E蛋白二聚体中一个E蛋白的DI以及DI与DII的连接区域,Z23主要结合DIII,同时插入到相邻两个E蛋白二聚体的沟槽中。三株抗体通过结合E蛋白的不同结构域影响膜融合过程中E蛋白构象变化从而影响病毒感染,同时Z23也有可能阻断ZIKV与受体的结合进而阻止ZIKV感染。其中,两株抗体(Z3L1和Z23)特异性阻断ZIKV感染,对于登革热等黄病毒没有交叉反应,有望进一步开发成药物,相关临床前研究正在进行并获得专利保护,为人类防治ZIKV提供了重要的抗体药物支撑。

抗原特异性免疫球蛋白及单克隆抗体在新生突发传染病应急治疗中起着重要作用。SARS、H5N1等康复病人血清可以有效治疗重症患者。然而这种血清依赖于康复者数量,限制其大规模使用。这一研究建立的B细胞单细胞测序技术能够从康复者中快速分离鉴定出抗原特异的中和抗体,并在短时间内达到规模化生产,提供大量的有效的应急抗体。同时通过对感染病人中和抗体产生机制及表位的确立,进一步指导疫苗的设计和研发。这一技术平台的建立对于我国应对新生突发传染病的暴发、保障国民健康及社会稳定具有重要意义。

Qihui Wang, Huabing Yang, Xiaoqing Liu, et al.Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus.Science Translational Medicine.2016 Dec 14.

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    2017-02-11 天涯183

    最新研究进展

    0

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    2017-02-11 Dr.jerry

    不错,学习了

    0

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