Nat Commun| 微生物所合作在抗基孔肯雅病毒中和抗体及作用机制研究中取得进展

基孔肯雅热是一种由基孔肯雅病毒（CHIKV）引起的、经蚊媒传播的人畜共患急性病毒性疾病，该病毒归类于披膜病毒科甲病毒属。尽管目前已有两款CHIKV疫苗在海外获批，但全球范围内仍缺乏获批的特异性抗病毒药物。鉴于此，在暴露后预防以及免疫受损人群的治疗方面，仍存在显著的未满足临床需求。

近日，昌平实验室严景华团队、中国科学院微生物研究所高福院士团队以及衢州疾控中心占炳东团队合作在Nature Communications发表题为“Neutralizing antibodies against Chikungunya virus ａｎｄ structural elucidation of their mechanism of action” 研究论文。研究人员从一名CHIKV感染康复者外周血记忆B细胞中筛选获得一组人源单克隆抗体，经系统评估后鉴定出两株高效中和抗体C34与C37。两者在体外呈强中和活性，在免疫缺陷小鼠致死性攻毒模型中，无论治疗组（感染后24 h给药）还是预防组（感染前24 h给药），均显著降低足跖肿胀，并实现100%存活。

为阐明抗体的分子机制，研究人员采用冷冻电镜（cryo-EM）与X射线晶体学技术，解析了抗体与病毒样颗粒（VLP）或E1–E2异源二聚体的复合物结构。结果显示，抗体结合在E2的一个关键表位，该表位跨越E2的B结构域与A–B连接区域，并涉及E1残基，核心残基为D250与K252。两株抗体紧密结合该区域，解释了其高亲和力与强中和表型。

图. C34与C37通过受体Mxra8颈部区阻断的结构机制

功能与结构分析揭示，抗体通过三重协同机制发挥中和作用：（1）附着阻断：C34/C37在相邻刺突与Mxra8茎部产生位阻，降低VLP与Mxra8阳性细胞的结合；（2）构象限制：抗体稳定E1/E2构象，限制E1融合环暴露，抑制膜融合；（3）颗粒交联：IgG在二、五重轴附近交联病毒颗粒，减少病毒扩散。

研究表明，康复者来源的人源抗体通过“受体茎部阻断+融合抑制+颗粒交联”多通路策略有效拦截CHIKV。E2 B域—A–B连接区域与E3脱落构象热点为抗体药物优化与结构疫苗设计提供了关键靶点，同时，Mxra8茎部阻断策略为开发广谱抗体干预提供了新路径。

Abstract 

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes febrile illness and acute or chronic arthritis. Most therapeutics are still in the pre-clinical stage. In this study, we report the isolation of two neutralizing antibodies, C34 and C37, from a convalescent patient and investigate their mechanisms of action. Both C34 and C37 exhibit high neutralizing activities in vitro and demonstrate protective effects against CHIKV in a female mouse model. Our functional and structural studies reveal a mechanism that inhibits multiple stages of the virus infection cycle. Both antibodies bind with high affinity to an epitope spanning E2, E1, and the connecting β-strands, facilitating intra- and inter-virion crosslinking. Cryo-EM structures additionally identify a minor patch located beneath the E3 binding site on E2, which is allosterically exposed upon E3 dissociation during virus maturation. Functional and structural data further suggest that binding to the CHIKV receptor, Mxra8, is obstructed due to a clash between the antibodies and the stalk region of Mxra8. Our results highlight the potential of antibody-based therapeutics against CHIKV and elucidate the mechanisms of monoclonal antibody protection.

原文链接

https://www.nature.com/articles/s41467-025-64687-2