PDF(Pubmed)
Abstract：
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus that causes severe viral hemorrhagic fever and thrombocytopenia syndrome with a fatality rate of up to 30%. No licensed vaccines or therapeutics are currently available for humans. Here, we develop seven monoclonal antibodies (mAbs) against SFTSV surface glycoprotein Gn. Mechanistic studies show that three neutralizing mAbs (S2A5, S1G3, and S1H7) block multiple steps during SFTSV infection, including viral attachment and membrane fusion, whereas another neutralizing mAb (B1G11) primarily inhibits the viral attachment step. Epitope binning and X-ray crystallographic analyses reveal four distinct antigenic sites on Gn, three of which have not previously been reported, corresponding to domain I, domain II, and spanning domain I and domain II. One of the most potent neutralizing mAbs, S2A5, binds to a conserved epitope on Gn domain I and broadly neutralizes infection of six SFTSV strains corresponding to genotypes A to F. A single dose treatment of S2A5 affords both pre- and post-exposure protection of mice against lethal SFTSV challenge without apparent weight loss. Our results support the importance of glycoprotein Gn for eliciting a robust humoral response and pave a path for developing prophylactic and therapeutic antibodies against SFTSV infection.
摘要：
严重发热伴血小板减少综合征病毒（SFTSV）是一种新兴的布尼亚病毒，可引起严重的病毒性出血热和血小板减少综合征，病死率高达30％。目前没有许可的疫苗或疗法可用于人类。这里,我们开发了七种抗SFTSV表面糖蛋白Gn的单克隆抗体（mAb）。机制研究表明，三种中和单克隆抗体（S2A5，S1G3和S1H7）阻断SFTSV感染过程中的多个步骤，包括病毒附着和膜融合，而另一种中和mAb（B1G11）主要抑制病毒附着步骤。表位分级和X射线晶体学分析揭示了Gn上四个不同的抗原位点，其中三个以前没有报道过，对应于域I，域II,跨越域I和域II。最有效的中和单克隆抗体之一，S2A5与Gn结构域I上的保守表位结合,并广泛中和对应于基因型A至F的6种SFTSV菌株的感染。S2A5的单剂量处理提供小鼠在暴露前和暴露后针对致死性SFTSV攻击的保护,而没有明显的体重减轻。我们的结果支持糖蛋白Gn引起强大的体液反应的重要性，并为开发针对SFTSV感染的预防性和治疗性抗体铺平了道路。
