Chikungunya virus (CHIKV) is a re-emerging arthropod-borne alphavirus and a serious threat to human health. Therefore, efforts toward elucidating how this virus causes disease and the molecular mechanisms underlying steps of the viral replication cycle are crucial. Using an in vivo transmission system that allows intra-host evolution, we identified an emerging CHIKV variant carrying a mutation in the E1 glycoprotein (V156A) in the serum of mice and saliva of mosquitoes. E1 V156A has since emerged in humans during an outbreak in Brazil, co-occurring with a second mutation, E1 K211T, suggesting an important role for these residues in CHIKV biology. Given the emergence of these variants, we hypothesized that they function to promote CHIKV infectivity and subsequent disease. Here, we show that E1 V156A and E1 K211T modulate virus attachment and fusion and impact binding to heparin, a homolog of heparan sulfate, a key entry factor on host cells. These variants also exhibit differential neutralization by anti-glycoprotein monoclonal antibodies, suggesting structural impacts on the particle that may be responsible for altered interactions at the host membrane. Finally, E1 V156A and E1 K211T exhibit increased titers in an adult arthritic mouse model and induce increased foot-swelling at the site of injection. Taken together, this work has revealed new roles for E1 where discrete regions of the glycoprotein are able to modulate cell attachment and swelling within the host.

中文翻译：

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E1-E1 间糖蛋白刺突界面处新出现的基孔肯雅病毒变种影响病毒附着和炎症

基孔肯雅病毒 (CHIKV) 是一种重新出现的节肢动物传播的甲病毒，对人类健康构成严重威胁。因此，努力阐明这种病毒如何引起疾病以及病毒复制周期的潜在步骤的分子机制至关重要。使用体内在允许宿主内进化的传输系统中，我们发现了一种新兴的 CHIKV 变体，其在小鼠血清和蚊子的唾液中携带 E1 糖蛋白 (V156A) 突变。E1 V156A 在巴西爆发期间出现在人类中，与第二个突变 E1 K211T 共同发生，表明这些残基在 CHIKV 生物学中的重要作用。鉴于这些变体的出现，我们假设它们的功能是促进 CHIKV 感染性和随后的疾病。在这里，我们展示了 E1 V156A 和 E1 K211T 调节病毒附着和融合并影响与肝素的结合，肝素是硫酸乙酰肝素的同源物，是宿主细胞的关键进入因子。这些变体还表现出抗糖蛋白单克隆抗体的差异中和作用，表明对颗粒的结构影响可能是导致宿主膜相互作用改变的原因。最后，E1 V156A 和 E1 K211T 在成年关节炎小鼠模型中表现出增加的滴度，并导致注射部位的足部肿胀增加。总之，这项工作揭示了 E1 的新作用，其中糖蛋白的离散区域能够调节宿主内的细胞附着和肿胀。