Molecular mechanism of potently neutralizing human monoclonal antibodies against severe fever with thrombocytopenia virus infection.

IF 4 2区 医学 Q2 VIROLOGY
Chuansong Quan, Kaixiao Nie, Dezhen Ma, Chao Su, Lianfeng Li, Wenjun Zheng, Chunhong Yin, Yiwen Wang, Peipei Yang, Dingkun Peng, Xin Liu, Weiwei Li, Weixiao Liu, Chao Shan, Jie Zheng, Di Liu, Hong Zhang, Michael J Carr, George F Gao, Jianxun Qi, Weifeng Shi
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引用次数: 0

Abstract

Although severe fever with thrombocytopenia syndrome (SFTS) was first described in China in 2009, the case fatality rate remains >40% among patients with multi-organ failure. To date, no antivirals specifically targeting SFTSV have been approved. We obtained several monoclonal antibodies (mAbs) from SFTS survivors by single-cell RNA-seq. Neutralization and animal experiments were applied to assess the effects of these mAbs in vitro and in vivo, and co-crystal structures with SFTSV-Gn glycoproteins were determined by X-ray crystallography. The mAbs SD4, SD12, and SD22 targeted the SFTSV-Gn with high neutralizing activities, and, remarkably, SD4 and SD22 exhibited KD values in the range of 32-83 pM for different viral genotypes. Notably, a single administration (20 mg/kg) of SD4 and SD22 showed 100% protection in mice at day 3 post-inoculation (dpi). Importantly, SD4 also provided 60% protection at a lower dose (0.3 mg/kg) when administered at 3 dpi. The crystallographic structures of SD4, SD22, and SD12 with Gn were determined at 3.3 Å, 2.8 Å, and 2.4 Å, respectively, which revealed that they recognized a conserved antigenic epitope around the hexon wellhead edge. These human-derived mAbs have significant therapeutic potential for severe SFTS cases and provide a basis for rational antibody-based vaccine designs and clinical trials.

Importance: The incidence of severe fever with thrombocytopenia syndrome (SFTS) has been increasing in Asia in recent years; however, no specific antiviral agents have been approved to date. Herein, we report a panel of anti-SFTSV Gn monoclonal antibodies (mAbs) with excellent neutralizing capacities and remarkable therapeutic potential in vitro and in vivo in a mouse model. In addition, crystallographic structures of mAbs complexed with Gn were resolved with atomic resolution (2.4 Å-3.3 Å), revealing a conserved antigenic epitope near the hexon wellhead edge. In sum, the neutralizing antibodies reported in the present study have significant therapeutic potential, paving the way for effective treatment of severe SFTS patients.

强中和性人单克隆抗体抗发热伴血小板减少病毒感染的分子机制。
尽管重症发热伴血小板减少综合征(SFTS)于2009年首次在中国被发现,但在多器官衰竭患者中,病死率仍高达40%。迄今为止,还没有专门针对SFTSV的抗病毒药物被批准。我们通过单细胞RNA-seq从SFTS幸存者中获得了几种单克隆抗体(mab)。通过中和实验和动物实验评估这些单克隆抗体在体外和体内的作用,并通过x射线晶体学检测其与SFTSV-Gn糖蛋白的共晶结构。单克隆抗体SD4、SD12和SD22对SFTSV-Gn具有较高的中和活性,且在不同的病毒基因型中,SD4和SD22的KD值在32 ~ 83 pM之间。值得注意的是,单次给药(20 mg/kg) SD4和SD22在小鼠接种后第3天(dpi)显示出100%的保护作用。重要的是,当以3 dpi给药时,SD4在较低剂量(0.3 mg/kg)下也提供60%的保护。SD4、SD22和SD12与Gn的晶体结构分别在3.3 Å、2.8 Å和2.4 Å处测定,这表明它们在六联体井口边缘识别了一个保守的抗原表位。这些人源性单克隆抗体对严重SFTS病例具有显著的治疗潜力,为合理的抗体疫苗设计和临床试验提供了基础。重要性:近年来,亚洲的发热伴血小板减少综合征(SFTS)发病率呈上升趋势;然而,迄今为止还没有特定的抗病毒药物被批准。在此,我们报道了一组抗sftsv Gn单克隆抗体(mab),它们在体外和体内小鼠模型中具有出色的中和能力和显着的治疗潜力。此外,用原子分辨率(2.4 Å-3.3 Å)分析了与Gn络合的单克隆抗体的晶体结构,发现在六联体井口边缘附近有一个保守的抗原表位。综上所述,本研究报道的中和抗体具有显著的治疗潜力,为重症SFTS患者的有效治疗铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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