Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
J Virol. 2019 May 29;93(12). doi: 10.1128/JVI.00113-19. Print 2019 Jun 15.
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus. Recent ZIKV outbreaks have produced serious human disease, including neurodevelopmental malformations (congenital Zika syndrome) and Guillain-Barré syndrome. These outcomes were not associated with ZIKV infection prior to 2013, raising the possibility that viral genetic changes could contribute to new clinical manifestations. All contemporary ZIKV isolates encode an N-linked glycosylation site in the envelope (E) protein (N154), but this glycosylation site is absent in many historical ZIKV isolates. Here, we investigated the role of E protein glycosylation in ZIKV pathogenesis using two contemporary Asian-lineage strains (H/PF/2013 and PRVABC59) and the historical African-lineage strain (MR766). We found that glycosylated viruses were highly pathogenic in mice. In contrast, nonglycosylated viruses were attenuated, producing lower viral loads in the serum and brain when inoculated subcutaneously but remaining neurovirulent when inoculated intracranially. These results suggest that E glycosylation is advantageous in the periphery but not within the brain. Accordingly, we found that glycosylation facilitated infection of cells expressing the lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) or DC-SIGN-related (DC-SIGNR), suggesting that inefficient infection of lectin-expressing leukocytes could contribute to the attenuation of nonglycosylated ZIKV in mice. It is unclear why the ability of Zika virus (ZIKV) to cause serious disease, including Guillain-Barré syndrome and birth defects, was not recognized until recent outbreaks. One contributing factor could be genetic differences between contemporary ZIKV strains and historical ZIKV strains. All isolates from recent outbreaks encode a viral envelope protein that is glycosylated, whereas many historical ZIKV strains lack this glycosylation. We generated nonglycosylated ZIKV mutants from contemporary and historical strains and evaluated their virulence in mice. We found that nonglycosylated viruses were attenuated and produced lower viral loads in serum and brains. Our studies suggest that envelope protein glycosylation contributes to ZIKV pathogenesis, possibly by facilitating attachment to and infection of lectin-expressing leukocytes.
寨卡病毒（ZIKV）是一种新兴的蚊媒黄病毒。最近的寨卡病毒爆发导致了严重的人类疾病，包括神经发育畸形（先天性寨卡综合征）和格林-巴利综合征。这些结果与 2013 年之前的寨卡病毒感染无关，这表明病毒遗传变化可能导致新的临床表现。所有当代寨卡病毒分离株的包膜（E）蛋白中都含有一个 N 连接糖基化位点（N154），但许多历史寨卡病毒分离株中不存在这个糖基化位点。在这里，我们使用两株当代亚洲谱系株（H/PF/2013 和 PRVABC59）和一株历史非洲谱系株（MR766）研究了 E 蛋白糖基化在寨卡病毒发病机制中的作用。我们发现，糖基化病毒在小鼠中具有高度致病性。相比之下，非糖基化病毒则减弱，皮下接种时血清和脑中的病毒载量较低，但脑内接种时仍具有神经毒性。这些结果表明，E 糖基化在外周组织中是有利的，但在脑内则不然。因此，我们发现糖基化促进了表达树突状细胞特异性细胞间黏附分子-3 捕获非整合素（DC-SIGN）或 DC-SIGN 相关（DC-SIGNR）的细胞感染，这表明糖基化效率低下的白细胞感染可能导致非糖基化寨卡病毒在小鼠中的减弱。目前还不清楚为什么直到最近的疫情爆发，寨卡病毒（ZIKV）导致严重疾病的能力，包括格林-巴利综合征和出生缺陷，才被人们认识到。一个促成因素可能是当代寨卡病毒株与历史寨卡病毒株之间的遗传差异。所有最近爆发的分离株都编码一种糖基化的病毒包膜蛋白，而许多历史寨卡病毒株则缺乏这种糖基化。我们从当代和历史株中生成了非糖基化的寨卡病毒突变体，并在小鼠中评估了它们的毒力。我们发现，非糖基化病毒减弱，血清和脑中的病毒载量较低。我们的研究表明，包膜蛋白糖基化有助于寨卡病毒的发病机制，可能是通过促进与表达凝集素的白细胞的附着和感染。
