Kostyuchenko Victor A, Chew Pau Ling, Ng Thiam-Seng, Lok Shee-Mei
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
J Virol. 2014 Jan;88(1):477-82. doi: 10.1128/JVI.02641-13. Epub 2013 Oct 23.
Dengue virus (DENV), a mosquito-borne virus, is responsible for millions of cases of infections worldwide. There are four DENV serotypes (DENV1 to -4). After a primary DENV infection, the antibodies elicited confer lifetime protection against that DENV serotype. However, in a secondary infection with another serotype, the preexisting antibodies may cause antibody-dependent enhancement (ADE) of infection of macrophage cells, leading to the development of the more severe form of disease, dengue hemorrhagic fever. Thus, a safe vaccine should stimulate protection against all dengue serotypes simultaneously. To facilitate the development of a vaccine, good knowledge of different DENV serotype structures is crucial. Structures of DENV1 and DENV2 had been solved previously. Here we present a near-atomic resolution cryo-electron microscopy (cryo-EM) structure of mature DENV4. Comparison of the DENV4 structure with similar-resolution cryo-EM structures of DENV1 and DENV2 showed differences in surface charge distribution, which may explain their differences in binding to cellular receptors, such as heparin. Also, observed variations in amino acid residues involved in interactions between envelope and membrane proteins on the virus surface correlate with their ability to undergo structural changes at higher temperatures.
登革病毒（DENV）是一种蚊媒病毒，在全球范围内导致数百万例感染病例。有四种登革病毒血清型（DENV1至DENV4）。初次感染登革病毒后，所产生的抗体可提供针对该血清型的终身保护。然而，在再次感染另一种血清型时，先前存在的抗体可能会导致巨噬细胞感染的抗体依赖性增强（ADE），从而引发更严重的疾病形式——登革出血热。因此，一种安全的疫苗应能同时刺激针对所有登革病毒血清型的保护作用。为促进疫苗的研发，深入了解不同登革病毒血清型的结构至关重要。登革病毒1型和2型的结构此前已得到解析。在此，我们展示了成熟登革病毒4型的近原子分辨率冷冻电子显微镜（cryo-EM）结构。将登革病毒4型的结构与登革病毒1型和2型具有相似分辨率的冷冻电子显微镜结构进行比较，结果显示表面电荷分布存在差异，这可能解释了它们在与细胞受体（如肝素）结合方面的差异。此外，观察到的病毒表面包膜蛋白与膜蛋白之间相互作用所涉及的氨基酸残基的变化，与其在较高温度下发生结构变化的能力相关。
