Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen.
Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen.
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DOI：
10.1128/mbio.02531-20
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Doores KJ
中科院分区：
文献类型：
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作者：
Rissanen I;Krumm SA;Stass R;Whitaker A;Voss JE;Bruce EA;Rothenberger S;Kunz S;Burton DR;Huiskonen JT;Botten JW;Bowden TA;Doores KJ
汉坦病毒是一组新兴的病原体，能够在人畜共患传播给人类时引起严重疾病。成熟的汉他病毒表面呈现两种糖蛋白Gn和Gc的高阶四聚体组装体，其负责协商宿主细胞进入并构成关键的治疗靶标。在这里，我们证明了重组衍生的Gn从汉滩病毒（HTNV）elevates中和抗体反应（血清稀释，抑制50%的感染[ID 50]，1：200至1：850）在动物模型。使用抗原特异性B细胞分选，我们分离出表现出中和和非中和活性的单克隆抗体（mAb），分别称为mAb HTN-Gn 1和mAb nnHTN-Gn 2。晶体学分析揭示，这些mAb靶向HTNV Gn胞外域的N-末端区域的不同位点处的空间上不同的表位。表位映射到高阶（Gn-Gc）4棘波模型上支持mAb HTN-Gn 1表位的免疫可及性，这一假设通过抗体与病毒样颗粒的电子冷冻断层扫描得到证实。这些数据定义了可以在免疫原设计中靶向的汉他病毒Gn的天然暴露区域。
Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design.
DOI：
10.3791/51714
发表时间：
2014-10-21
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Huiskonen JT;Parsy ML;Li S;Bitto D;Renner M;Bowden TA
通讯作者：
Bowden TA