Viral neutralization by antibody-imposed physical disruption
Viral neutralization by antibody-imposed physical disruption
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通过抗体施加的物理破坏来中和病毒
DOI：
10.1073/pnas.1916028116
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发表时间：
2019-12-26
影响因子：
11.1
通讯作者：
Xia，Ningshao
中科院分区：
文献类型：
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作者：
Zheng，Qingbing;Jiang，Jie;Xia，Ningshao
在病原体入侵过程中，中和抗体（nAbs）参与调节免疫清除和引起宿主保护性反应。我们先前报道了一种高效抗HEV的nAb 8 C11，HEV是一种具有二十面体衣壳的RNA病毒，与大量急性肝炎相关。结构分析表明，8 C11与HEV VLP的结合将导致与衣壳的巨大空间冲突。Cryo-EM分析表明，8 C11结合导致早期阶段（约15 min）VLP外缘的完全紊乱，并导致HEV VLP在2 h内解离成同源二聚体。对于天然HEV病毒粒子也观察到类似的8 C11介导的解离。我们的研究结果对病毒中和机制进行了分类，并提出了产生8 C11样抗体的策略。在适应性免疫中，生物体产生中和抗体（nAb）以消除入侵的病原体。在这里，我们探讨了病毒中和是否可以通过nAb结合后病毒的物理破坏来实现。我们报告了针对戊型肝炎病毒（HEV）的强效nAb 8 C11的中和机制，HEV是一种与大量急性肝炎相关的无包膜正义单链RNA病毒。8 C11结合在HEV病毒样颗粒（VLP）的突起刺突的侧面，并导致抗体和衣壳之间的巨大物理碰撞，在2小时内将VLP解离成同源二聚体种类。冷冻电子显微镜重建的解离中间体在早期（15分钟）的阶段发现涂抹突起尖峰和二十面体对称性的损失与衣壳核心保持不变。这种结构破坏导致在超离心沉淀物中仅存在少数天然HEV病毒体并暴露病毒基因组。从概念上讲，我们提出了一种策略，以提高碰撞诱导的nAb对单一的穗部分，功能在整个病原体的位置，其中相邻的空间不能容纳抗体的背景下。这一基本原理可能有助于独特的疫苗开发和抗微生物抗体设计。
Significance During pathogenic invasion, neutralizing antibodies (nAbs) are involved in regulating immune clearance and evoking the host-protective response. We previously reported a highly potent nAb 8C11 against HEV, an RNA virus with an icosahedral capsid and associated with abundant acute hepatitis. Structural analysis demonstrates that the binding of 8C11 to HEV VLPs would result in tremendous spatial clashing with the capsid. Cryo-EM analysis showed that 8C11 binding leads to complete disorder of the outer rim of the VLP at earlier stages (∼15 min) and causes the dissociation of HEV VLPs into homodimer species within 2 h. Similar 8C11-mediated dissociation was observed for the native HEV virion. Our results categorize a viral neutralization mechanism and suggest a strategy to generate 8C11-like antibodies. In adaptive immunity, organisms produce neutralizing antibodies (nAbs) to eliminate invading pathogens. Here, we explored whether viral neutralization could be attained through the physical disruption of a virus upon nAb binding. We report the neutralization mechanism of a potent nAb 8C11 against the hepatitis E virus (HEV), a nonenveloped positive-sense single-stranded RNA virus associated with abundant acute hepatitis. The 8C11 binding flanks the protrusion spike of the HEV viruslike particles (VLPs) and leads to tremendous physical collision between the antibody and the capsid, dissociating the VLPs into homodimer species within 2 h. Cryo-electron microscopy reconstruction of the dissociation intermediates at an earlier (15-min) stage revealed smeared protrusion spikes and a loss of icosahedral symmetry with the capsid core remaining unchanged. This structural disruption leads to the presence of only a few native HEV virions in the ultracentrifugation pellet and exposes the viral genome. Conceptually, we propose a strategy to raise collision-inducing nAbs against single spike moieties that feature in the context of the entire pathogen at positions where the neighboring space cannot afford to accommodate an antibody. This rationale may facilitate unique vaccine development and antimicrobial antibody design.