Structures of Coxsackievirus A16 Capsids with Native Antigenicity: Implications for Particle Expansion, Receptor Binding, and Immunogenicity.
Structures of Coxsackievirus A16 Capsids with Native Antigenicity: Implications for Particle Expansion, Receptor Binding, and Immunogenicity.
复制标题
具有天然抗原性的柯萨奇病毒 A16 衣壳的结构：对颗粒扩展、受体结合和免疫原性的影响。
DOI：
10.1128/jvi.01102-15
复制
发表时间：
2015-10
影响因子：
5.4
通讯作者：
Stuart DI
中科院分区：
文献类型：
--
作者：
Ren J;Wang X;Zhu L;Hu Z;Gao Q;Yang P;Li X;Wang J;Shen X;Fry EE;Rao Z;Stuart DI
肠道病毒71型和柯萨奇病毒A16型是手足口病流行的主要原因。手足口病每年影响中国100多万儿童，导致数百人死亡。尽管针对EV71的疫苗已经取得了进展，但事实证明，CVA16疫苗的开发更具挑战性，而且EV71疫苗没有提供有用的交叉保护，尽管这两种病毒的衣壳蛋白有大约80%的序列相同。具有非天然抗原性的衣壳扩张形式的结构细节现在已被很好地了解，但天然抗原型CVA16的高分辨率信息一直缺乏。在这里，我们用成熟的和自然的空CVA16颗粒以及昆虫细胞中产生的空的重组病毒样颗粒的高分辨率X射线结构来补救这一点，CVA16是一种潜在的疫苗抗原。这三种结构都是未膨胀的天然颗粒，抗原性相同。重组颗粒招募了一种脂类部分来稳定天然的抗原状态，这与自然病毒感染中使用的不同。正如预期的那样，成熟的CVA16病毒与EV71相似；然而，结构和免疫原性比较突出了可能对疫苗生产产生影响的差异。重要手足口病是对亚太国家儿童的严重公共健康威胁，导致数百万病例。EV71和CVA16是这种疾病的两种主要病原体，虽然通常是轻微的，但可导致严重的神经并发症，导致数百人死亡。EV71疫苗不能提供对CVA16的保护。因此，迫切需要一种CVA16疫苗或EV71/CVA16双价疫苗。我们报道了成熟的CVA16病毒的原子结构，一种天然的空颗粒，以及一种不包含病毒基因组的重组CVA16病毒样颗粒。这三种颗粒具有相似的结构和相同的抗原性。在昆虫细胞(一种适合制造疫苗抗原的系统)中产生的重组颗粒通过从昆虫细胞中招募一种不同于病毒在正常感染中使用的小分子来稳定下来。我们提供了与EV71的结构和免疫原性比较，以促进基于结构的药物设计和疫苗开发。
Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the primary causes of the epidemics of hand-foot-and-mouth disease (HFMD) that affect more than a million children in China each year and lead to hundreds of deaths. Although there has been progress with vaccines for EV71, the development of a CVA16 vaccine has proved more challenging, and the EV71 vaccine does not give useful cross-protection, despite the capsid proteins of the two viruses sharing about 80% sequence identity. The structural details of the expanded forms of the capsids, which possess nonnative antigenicity, are now well understood, but high resolution information for the native antigenic form of CVA16 has been missing. Here, we remedy this with high resolution X-ray structures of both mature and natural empty CVA16 particles and also of empty recombinant viruslike particles of CVA16 produced in insect cells, a potential vaccine antigen. All three structures are unexpanded native particles and antigenically identical. The recombinant particles have recruited a lipid moiety to stabilize the native antigenic state that is different from the one used in a natural virus infection. As expected, the mature CVA16 virus is similar to EV71; however, structural and immunogenic comparisons highlight differences that may have implications for vaccine production. IMPORTANCE Hand-foot-and-mouth disease is a serious public health threat to children in Asian-Pacific countries, resulting in millions of cases. EV71 and CVA16 are the two dominant causative agents of the disease that, while usually mild, can cause severe neurological complications, leading to hundreds of deaths. EV71 vaccines do not provide protection against CVA16. A CVA16 vaccine or bivalent EV71/CVA16 vaccine is therefore urgently needed. We report atomic structures for the mature CVA16 virus, a natural empty particle, and a recombinant CVA16 virus-like particle that does not contain the viral genome. All three particles have similar structures and identical antigenicity. The recombinant particles, produced in insect cells (a system suitable for making vaccine antigen), are stabilized by recruiting from the insect cells a small molecule that is different from that used by the virus in a normal infection. We present structural and immunogenic comparisons with EV71 to facilitate structure-based drug design and vaccine development.