GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection
GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection
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DOI：
10.1126/sciadv.aaw9535
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发表时间：
2019-07-01
期刊：
影响因子：
13.6
通讯作者：
Garrison, Aura R.
中科院分区：
文献类型：
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作者：
Golden, Joseph W.;Shoemaker, Charles J.;Garrison, Aura R.
克里米亚-刚果出血热病毒（CCHFV）是人类重要的病原体。有限的证据表明，抗体可以保护人类免受致命的CCHFV疾病，但抗体的保护功效从未在成年动物模型中进行过评估。在这里，我们使用成年小鼠来研究糖蛋白靶向中和和非中和单克隆抗体（mAb）对CCHFV感染的保护作用。我们鉴定了一种单一的非中和抗体（mAb-13 G8），当在病毒暴露前开始治疗时，其保护成年I型干扰素缺陷小鼠>90%，当在病毒暴露后施用时，其保护成年I型干扰素缺陷小鼠>60%。已知保护新生小鼠免受致死性CCHFV感染的中和抗体不能提供保护，无论免疫球蛋白G亚类。mAb-13 G8的靶点被鉴定为GP 38，其是来自CCHFV糖蛋白前体多聚蛋白的多种蛋白水解切割的糖蛋白之一。本研究揭示了GP 38作为限制CCHFV致病的重要抗体靶点，并为开发针对人类CCHFV的免疫治疗药物奠定了基础。
Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. Limited evidence suggests that antibodies can protect humans against lethal CCHFV disease but the protective efficacy of antibodies has never been evaluated in adult animal models. Here, we used adult mice to investigate the protection provided against CCHFV infection by glycoprotein-targeting neutralizing and non-neutralizing monoclonal antibodies (mAbs). We identified a single non-neutralizing antibody (mAb-13G8) that protected adult type I interferon-deficient mice >90% when treatment was initiated before virus exposure and >60% when administered after virus exposure. Neutralizing antibodies known to protect neonatal mice from lethal CCHFV infection failed to confer protection regardless of immunoglobulin G subclass.The target of mAb-13G8 was identified as GP38, one of multiple proteolytically cleaved glycoproteins derived from the CCHFV glycoprotein precursor polyprotein. This study reveals GP38 as an important antibody target for limiting CCHFV pathogenesis and lays the foundation to develop immunotherapeutics against CCHFV in humans.