Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex.
Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex.
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克里米亚-刚果出血热病毒融合前异三聚体糖蛋白复合物的工程、结构和免疫原性。
DOI：
10.1101/2024.04.20.590419
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
McLellan,JasonS
中科院分区：
文献类型：
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作者：
McFadden,Elizabeth;Monticelli,StephanieR;Wang,Albert;Ramamohan,AjitR;Batchelor,ThomasG;Kuehne,AnaI;Bakken,RussellR;Tse,AlexandraL;Chandran,Kartik;Herbert,AndrewS;McLellan,JasonS
克里米亚-刚果出血热病毒（CCHFV）是一种蜱传病毒，可引起人类严重疾病，病死率为10- 40%。尽管CCHFV糖蛋白GP 38和Gc的结构提供了对病毒进入和中和和保护性抗体的确定表位的了解，但糖蛋白Gn的结构及其与GP 38和Gc的相互作用仍然是难以捉摸的。在这里，我们使用结构指导的蛋白质工程来产生稳定的GP 38-Gn-Gc异三聚体糖蛋白复合物（GP 38-GnH-DS-Gc）。该复合物的cryo-EM结构为GP 38在病毒表面上的结合提供了分子基础，揭示了Gn的结构，并证明GP 38-Gn抑制了融合前构象中的Gc融合环，这是由连接到Gn的N-连接聚糖促进的。用GP 38-GnH-DS-Gc免疫小鼠，对致死性IbAr 10200攻击的保护率为40%。这些数据定义了GP 38-Gn-Gc原聚体的结构，并为结构指导的疫苗抗原开发提供了模板。
Crimean–Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause severe disease in humans with case fatality rates of 10–40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we used structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-GnH-DS-Gc). A cryo-EM structure of this complex provides the molecular basis for GP38’s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-GnH-DS-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.