Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody-猫眼课题宝

DOI：

10.1101/2020.04.17.029876

发表时间：

2020-04

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

I. Rissanen;R. Stass;S. A. Krumm;J. Seow;R. Hulswit;G. Paesen;J. Hepojoki;O. Vapalahti;Å. Lundkvist;O. Reynard;V. Volchkov;K. Doores;J. Huiskonen;T. Bowden

汉坦病毒表面的 Gn 和 Gc 糖蛋白刺突复合物的复杂晶格有助于宿主细胞进入，并且是中和抗体介导的免疫反应的主要目标。在这里，通过研究感染普马拉病毒（PUUV）后在银行田鼠储存宿主中产生的中和单克隆抗体（mAb 4G2），我们提供了分子水平的见解，了解抗体介导的汉坦病毒糖蛋白晶格靶向如何有效中和病毒。晶体分析表明，mAb 4G2 在融合前状态下与 Gc 上的多结构域位点结合，并且 Fab 结合与进入宿主细胞所需的 Gc 构象变化不相容。用 Fab 4G2 处理的 PUUV 样颗粒的冷冻电子显微镜表明，该抗体在 Gn-Gc 晶格断裂处与单体 Gc 结合，突出了成熟汉坦病毒表面上 Gc 单体的免疫可及性以及高阶晶格组装的可塑性。这项工作为合理化抗体介导的汉坦病毒靶向提供了基于结构的蓝图。

The intricate lattice of Gn and Gc glycoprotein spike complexes at the surface of hantaviruses facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Here, through study of a neutralizing monoclonal antibody (mAb 4G2) generated in a bank vole reservoir host following infection with Puumala virus (PUUV), we provide molecular-level insights into how antibody-mediated targeting of the hantaviral glycoprotein lattice effectively neutralizes the virus. Crystallographic analysis reveals that mAb 4G2 binds to a multi-domain site on Gc in the pre-fusion state, and that Fab binding is incompatible with the conformational changes of the Gc that are required for host cell entry. Cryo-electron microscopy of PUUV-like particles treated with Fab 4G2 demonstrates that the antibody binds to monomeric Gc at breaks in the Gn-Gc lattice, highlighting the immunological accessibility of Gc monomers on the mature hantavirus surface and the plastic nature of the higher-order lattice assembly. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.

Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody

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