Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Cell Host Microbe. 2020 Mar 11;27(3):428-440.e9. doi: 10.1016/j.chom.2020.01.008. Epub 2020 Feb 18.
Alphaviruses are emerging, mosquito-transmitted RNA viruses with poorly understood cellular tropism and species selectivity. Mxra8 is a receptor for multiple alphaviruses including chikungunya virus (CHIKV). We discovered that while expression of mouse, rat, chimpanzee, dog, horse, goat, sheep, and human Mxra8 enables alphavirus infection in cell culture, cattle Mxra8 does not. Cattle Mxra8 encodes a 15-amino acid insertion in its ectodomain that prevents Mxra8 binding to CHIKV. Identical insertions are present in zebu, yak, and the extinct auroch. As other Bovinae lineages contain related Mxra8 sequences, this insertion likely occurred at least 5 million years ago. Removing the Mxra8 insertion in Bovinae enhances alphavirus binding and infection, while introducing the insertion into mouse Mxra8 blocks CHIKV binding, prevents infection by multiple alphaviruses in cells, and mitigates CHIKV-induced pathogenesis in mice. Our studies on how this insertion provides resistance to CHIKV infection could facilitate countermeasures that disrupt Mxra8 interactions with alphaviruses.
甲病毒是新兴的、经蚊子传播的 RNA 病毒，其细胞嗜性和种属选择性尚不清楚。Mxra8 是多种甲病毒的受体，包括基孔肯雅病毒 (CHIKV)。我们发现，虽然小鼠、大鼠、黑猩猩、狗、马、山羊、绵羊和人 Mxra8 的表达可使甲病毒在细胞培养中感染，但牛 Mxra8 不能。牛 Mxra8 在其胞外域编码 15 个氨基酸插入，阻止 Mxra8 与 CHIKV 结合。在瘤牛、牦牛和已灭绝的原牛中也存在相同的插入。由于其他牛科动物的谱系中含有相关的 Mxra8 序列，因此这种插入可能至少发生在 500 万年前。去除牛科动物 Mxra8 的插入可增强甲病毒的结合和感染，而将插入物引入小鼠 Mxra8 则可阻止 CHIKV 结合，防止多种甲病毒在细胞中感染，并减轻 CHIKV 诱导的小鼠发病机制。我们对这种插入如何提供对 CHIKV 感染的抗性的研究可以促进破坏 Mxra8 与甲病毒相互作用的对策。
