Neutralization Mechanisms of Two Highly Potent Antibodies against Human Enterovirus 71.
Neutralization Mechanisms of Two Highly Potent Antibodies against Human Enterovirus 71.
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DOI：
10.1128/mbio.01013-18
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发表时间：
2018-07-03
期刊：
影响因子：
6.4
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Zhu L;Xu K;Wang N;Cao L;Wu J;Gao Q;Fry EE;Stuart DI;Rao Z;Wang J;Wang X
尽管在卫生保健方面取得了重大进展，但肠道病毒感染的爆发每年仍困扰着亚太地区。肠病毒71 （EV71）引起手足口病（HFMD），目前尚无治疗方法。在这里，我们报告了两种新的抗体，A9和D6，能有效中和EV71。A9对EV71的50%中和浓度（neu50）值为0.1 nM，比D6低10倍。对中和机制的研究表明，A9与EV71的结合阻断了受体的结合，但也破坏了病毒衣壳结构的稳定性。相比之下，D6仅轻微破坏了衣壳的稳定性，但更有力地干扰了病毒与宿主细胞的附着。与EV71结合的A9和D6的冷冻电镜（cryo-EM）结构揭示了两种抗体识别的表位的位置和性质。尽管两种抗体识别的表位的某些区域重叠，但存在差异，从而导致效力和中和机制的不同。有趣的是，抗原表位的重叠区域包含了病毒用来结合SCARB2的位点，这解释了两种抗体阻断病毒-受体相互作用的原因。我们还确定了可能在调节EV71颗粒稳定性（包括颗粒完整性）中发挥作用的结构元件。本研究揭示的A9和D6表位的分子特征为合理设计抗病毒药物开辟了新的途径。在病毒感染过程中，人体产生中和抗体，在清除病毒中起决定性作用。从这项研究中，我们报告了两种新的，高效的中和抗体，A9和D6，针对肠病毒71 (EV71)，手足口病的病原体。这两种抗体都能阻止病毒进入宿主细胞，这是成功感染的重要一步。A9破坏病毒衣壳的稳定性，并破坏病毒衣壳在病毒基因组周围形成的外部保护层，同时也干扰病毒与宿主细胞的附着。相反，D6只能阻止病毒与其受体的结合。A9的中和机制是独特的，以前未观察到用于中和针对ev的抗体。我们在这项研究中报告的两种抗体有潜力发展成为治疗手足口病急需的治疗干预措施，亚太地区每年都有手足口病爆发的报告。
Despite significant advances in health care, outbreaks of infections by enteroviruses (EVs) continue to plague the Asia-Pacific region every year. Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), for which there are currently no therapeutics. Here, we report two new antibodies, A9 and D6, that potently neutralize EV71. A9 exhibited a 50% neutralizing concentration (neut50) value of 0.1 nM against EV71, which was 10-fold lower than that observed for D6. Investigation into the mechanisms of neutralization revealed that binding of A9 to EV71 blocks receptor binding but also destabilizes and damages the virus capsid structure. In contrast, D6 destabilizes the capsid only slightly but interferes more potently with the attachment of the virus to the host cells. Cryo-electron microscopy (cryo-EM) structures of A9 and D6 bound with EV71 shed light on the locations and nature of the epitopes recognized by the two antibodies. Although some regions of the epitopes recognized by the two antibodies overlap, there are differences that give rise to dissimilarities in potency as well as in the mechanisms of neutralization. Interestingly, the overlapping regions of the epitopes encompass the site that the virus uses to bind SCARB2, explaining the reason for the observed blocking of the virus-receptor interaction by the two antibodies. We also identified structural elements that might play roles in modulating the stability of the EV71 particles, including particle integrity. The molecular features of the A9 and D6 epitopes unveiled in this study open up new avenues for rationally designing antiviral drugs. During the course of viral infections, the human body produces neutralizing antibodies which play a defining role in clearing the virus. From this study, we report two new, highly potent neutralizing antibodies, A9 and D6, against enterovirus 71 (EV71), the causative agent of HFMD. Both antibodies prevent the virus from entering the host cell, a step that is important for establishing a successful infection. A9 destabilizes and damages the virus capsid that forms an outer protective covering around the genome of the virus, while also interfering with virus attachment to the host cells. In contrast, D6 only prevents binding of the virus to its receptor(s). The mechanism of neutralization of A9 is unique and has not been observed before for neutralizing antibodies targeting EVs. The two antibodies that we are reporting in this study have potential to be developed into much-needed therapeutic interventions for treatment of HFMD, outbreaks of which are reported every year in the Asia-Pacific region.