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 Ifnar1-/- 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.IMPORTANCE 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.

中文翻译：

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信封蛋白糖基化介导寨卡病毒的发病机理。

寨卡病毒（ZIKV）是一种新兴的蚊媒黄病毒。最近的ZIKV爆发已引起严重的人类疾病，包括神经发育畸形（先天性Zika综合征）和Guillain-Barré综合征。这些结果与2013年之前的ZIKV感染无关，这增加了病毒遗传变化可能有助于新的临床表现的可能性。所有当代ZIKV分离株都在包膜（E）蛋白（N154）中编码一个N-连接的糖基化位点，但是许多历史ZIKV分离株中都没有这个糖基化位点。在这里，我们调查了E蛋白糖基化在ZIKV发病机理中的作用，使用了两种当代亚洲谱系菌株（H / PF / 2013和PRVABC59）和历史悠久的非洲谱系菌株（MR766）。我们发现糖基化病毒在Ifnar1-/-小鼠中具有高致病性。相反，非糖基化病毒减毒，皮下接种时在血清和脑中产生较低的病毒载量，但颅内接种时仍保持神经毒力。这些结果表明，E糖基化在周围而不是在大脑内是有利的。因此，我们发现糖基化促进表达凝集素树突状细胞特异性细胞间粘附分子3的非整合素（DC-SIGN）或DC-SIGN相关（DC-SIGNR）表达凝集素的细胞的感染，提示表达凝集素的感染效率低下白血球可能会导致小鼠非糖基化ZIKV的减毒。重要信息目前尚不清楚为什么寨卡病毒（ZIKV）导致严重疾病的能力，包括Guillain-Barré综合征和先天缺陷，直到最近的爆发才被认识。一个促成因素可能是当代ZIKV菌株与历史ZIKV菌株之间的遗传差异。来自近期疫情的所有分离株均编码一种被糖基化的病毒包膜蛋白，而许多历史ZIKV株均缺乏这种糖基化。我们从当代和历史菌株中产生了非糖基化的ZIKV突变体，并评估了它们在小鼠中的毒性。我们发现非糖基化病毒减毒并在血清和大脑中产生较低的病毒载量。我们的研究表明，包膜蛋白糖基化可能通过促进附着和感染表达凝集素的白细胞而促进ZIKV发病。而许多历史ZIKV菌株都缺乏这种糖基化作用。我们从当代和历史菌株中产生了非糖基化的ZIKV突变体，并评估了它们在小鼠中的毒性。我们发现非糖基化病毒减毒并在血清和大脑中产生较低的病毒载量。我们的研究表明，包膜蛋白糖基化可能通过促进附着和感染表达凝集素的白细胞而促进ZIKV发病。而许多历史ZIKV菌株都缺乏这种糖基化作用。我们从当代和历史菌株中产生了非糖基化的ZIKV突变体，并评估了它们在小鼠中的毒性。我们发现非糖基化病毒减毒并在血清和大脑中产生较低的病毒载量。我们的研究表明，包膜蛋白糖基化可能通过促进附着和感染表达凝集素的白细胞而促进ZIKV发病。