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PNAS:科学家发现中国“蜱虫病”病毒的“阿喀琉斯之踵

2017-08-24 佚名 中国生物技术网

中国科学院微生物研究所高福团队与遗传与发育生物学研究所博士高峰首次解析了两种布尼亚病毒囊膜蛋白Gn的结构以及其中一种重要病原新布尼亚病毒(又称发热伴血小板减少综合征病毒,SFTSV)的Gn与中和抗体的复合物结构,为疫苗与抗病毒药物的研发提供了重要的理论依据。


图1. 白蛉属布尼亚病毒囊膜蛋白Gn在病毒表面锚定方式模式图


图2. 中和抗体Mab 4-5特异性识别SFTSV Gn的分子基础

布尼亚病毒是成员组成最多的古老的RNA病毒群之一,包括至少350个成员。其中有一些布尼亚病毒对人类健康具有重要威胁。然而,人类对于这类病毒知之甚少,其受体、侵入机制、病毒表面糖蛋白互作方式等问题至今都没有确定的答案。中国科学院微生物研究所高福团队与遗传与发育生物学研究所博士高峰首次解析了两种布尼亚病毒囊膜蛋白Gn的结构以及其中一种重要病原新布尼亚病毒(又称发热伴血小板减少综合征病毒,SFTSV)的Gn与中和抗体的复合物结构,为疫苗与抗病毒药物的研发提供了重要的理论依据。

根据国际病毒命名委员会(ICTV)的最新报告,原来的布尼亚病毒科升级为布尼亚病毒目,包含9个科。除已有的汉坦病毒属 (Hantavirus)、内罗病毒属 (Nairovirus)和番茄斑萎病毒属 (Tospovirus)直接升级为相应的科之外,原来的正布尼亚病毒属与新定义的草本病毒属一起组成新的病毒科Peribunyaviridae,白蛉属(Phlebovirus)与新增的Phasivirus、Goukovirus及Tenuivirus一起组成Phenuiviridae病毒科,同时还增加了Feraviridae、Fimoviridae、Jonviridae和Phasmaviridae四个科。本研究中涉及的新布尼亚病毒和裂谷热病毒(RVFV)均属于白蛉属。2007年起,我国河南、安徽、山东等地相继出现蜱虫咬人致死事件,其元凶就是新布尼亚病毒。该病毒由我国科学家于2010年分离得到,目前在日本、韩国等地也有感染病例报道。裂谷热病毒引发的裂谷热是一种经蚊虫媒介或接触传播的人畜共患病。裂谷热病毒感染可导致反刍动物流产,感染病人通常出现发热、头痛、出血、休克等症状,严重者甚至死亡。2016年我国出现1例裂谷热病毒感染输入病例。目前,仍没有针对这两种病毒的人用疫苗和有效药物。

布尼亚病毒是一种具有囊膜的单链RNA病毒,具有三个RNA片段(S,M和L)。其中M基因编码囊膜蛋白Gn和Gc,在病毒侵入宿主细胞的过程中起重要作用。前人的研究推测,Gn在病毒侵入宿主细胞过程中有可能起识别受体的作用。研究团队首次解析了裂谷热病毒和新布尼亚病毒囊膜蛋白Gn的头部区结构,发现这两种Gn的头部区的整体结构十分相似,均由三个亚结构域组成,但是亚结构域存在差异。对于SFTSV Gn全长蛋白的研究发现,该蛋白同时存在单体和二聚体两种形式。质谱分析和突变实验结果显示,靠近C末端的4个半胱氨酸是形成二硫键的关键位点,这4个半胱氨酸在5个布尼亚病毒属(按照ICTV最新分类分别为Hantaviridae, Nairoviridae, Tospoviridae病毒科和Phenuiviridae科白蛉属以及Peribunyaviridae科正布尼亚病毒属)的成员间非常保守,由此提出布尼亚病毒囊膜蛋白Gn在病毒表面以二聚体形式存在的模型(图1)。

研究人员进一步解析了SFTSV Gn与中和抗体MAb 4-5的复合物结构,发现Gn的domain III的α6螺旋是中和抗体MAb 4-5识别的关键表位(图2)。序列分析结果显示,该表位在白蛉属的其他布尼亚病毒中并不保守,解释了该中和抗体特异性结合SFTSV Gn,不结合RVFV Gn的原因。SFTSV Gn与抗体的复合物结构阐明了两者的作用模式,为疫苗及抗病毒药物的设计、抗体改造提供了理论依据。

相关研究结果在《美国国家科学院院刊》(PNAS)上在线发表。该项研究得到了科技部重大专项、中科院前沿科学重点研究项目、国家自然科学基金、中科院青年创新促进会等项目的资助。

原始出处:Yan Wu, Yaohua Zhu, Feng Gao, et al.  Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope. PNAS(2017).

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    2018-02-14 drwjr
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    2018-06-14 yxch36
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    2017-08-26 xfpan16
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    2017-08-26 nakerunner
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