Microbial Genomics Ph.D. Program, National Chung Hsing University and Academia Sinica, Taichung City, Taiwan.
Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung City, Taiwan.
Elife. 2018 Oct 18;7:e38970. doi: 10.7554/eLife.38970.
Dengue fever is caused by four different serotypes of dengue virus (DENV) which is the leading cause of worldwide arboviral diseases in humans. Virus-like particles (VLPs) containing flavivirus prM/E proteins have been demonstrated to be a potential vaccine candidate; however, the structure of dengue VLP is poorly understood. Herein VLP derived from DENV serotype-2 were engineered becoming highly matured (mD2VLP) and showed variable size distribution with diameter of ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm diameter possess a T = 1 icosahedral symmetry with a groove located within the E-protein dimers near the 2-fold vertices that exposed highly overlapping, cryptic neutralizing epitopes. Mice vaccinated with mD2VLP generated higher cross-reactive (CR) neutralization antibodies (NtAbs) and were fully protected against all 4 serotypes of DENV. Our results highlight the potential of 'epitope-resurfaced' mature-form D2VLPs in inducing quaternary structure-recognizing broad CR NtAbs to guide future dengue vaccine design.
登革热是由四种不同血清型的登革病毒（DENV）引起的，它是全球人类虫媒病毒病的主要病因。含有黄病毒前膜/包膜蛋白的病毒样颗粒（VLPs）已被证明是一种有潜力的疫苗候选物；然而，登革热 VLP 的结构仍不清楚。在此，我们对来自登革热病毒血清型 2 的 VLP 进行了工程改造，使其高度成熟（mD2VLP），并在冷冻电镜检查下显示出不同的粒径分布，直径约为 31nm，形成主要群体。此外，直径为 31nm 的 mD2VLP 颗粒具有 T=1 二十面体对称结构，在 E 蛋白二聚体附近的 2 倍顶点处有一条位于其中的凹槽，暴露出高度重叠的、隐匿的中和表位。用 mD2VLP 免疫的小鼠产生了更高的交叉反应（CR）中和抗体（NtAbs），并能完全抵抗所有 4 种血清型的 DENV。我们的结果强调了“表位重新出现”的成熟形式 D2VLP 在诱导识别四级结构的广泛 CR NtAbs 方面的潜力，为未来的登革热疫苗设计提供了指导。
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