Cryo-EM Structures of Eastern Equine Encephalitis Virus Reveal Mechanisms of Virus Disassembly and Antibody Neutralization
Cryo-EM Structures of Eastern Equine Encephalitis Virus Reveal Mechanisms of Virus Disassembly and Antibody Neutralization
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DOI：
10.1016/j.celrep.2018.11.067
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发表时间：
2018-12-11
期刊：
影响因子：
8.8
通讯作者：
Rossmann, Michael G.
中科院分区：
文献类型：
--
作者：
Hasan, S. Saif;Sun, Chengqun;Rossmann, Michael G.
甲病毒是引起关节炎和脑炎的包膜病原体。在这里，我们报告了东部马脑炎病毒 (EEEV) 的 4.4 埃冷冻电子显微镜 (cryo-EM) 结构，这是一种导致人类致命脑炎的甲病毒。我们的分析提供了有关病毒进入宿主细胞的见解。包膜蛋白 E2 显示出细胞附着因子硫酸乙酰肝素的结合位点。神秘 E2 聚糖的存在表明 EEEV 如何逃避表达凝集素的骨髓谱系细胞的监视，这些细胞是免疫系统的哨兵。根据 pH 值变化和衣壳与包膜蛋白的解离，推断出病毒进入后核衣壳核心释放和分解的机制。 EEEV衣壳结构显示病毒RNA基因组结合位点与核糖体结合位点相邻，用于基因组释放后病毒基因组翻译。使用源自中和抗体的五种 Fab-EEEV 复合物，我们的研究提供了对 EEEV 宿主细胞相互作用和与疫苗设计相关的保护性表位的见解。
Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Here, we report a 4.4-angstrom cryo-electron microscopy (cryo-EM) structure of eastern equine encephalitis virus (EEEV), an alphavirus that causes fatal encephalitis in humans. Our analysis provides insights into viral entry into host cells. The envelope protein E2 showed a binding site for the cellular attachment factor heparan sulfate. The presence of a cryptic E2 glycan suggests how EEEV escapes surveillance by lectin-expressing myeloid lineage cells, which are sentinels of the immune system. A mechanism for nucleocapsid core release and disassembly upon viral entry was inferred based on pH changes and capsid dissociation from envelope proteins. The EEEV capsid structure showed a viral RNA genome binding site adjacent to a ribosome binding site for viral genome translation following genome release. Using five Fab-EEEV complexes derived from neutralizing antibodies, our investigation provides insights into EEEV host cell interactions and protective epitopes relevant to vaccine design.