An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis.,Cell Host & Microbe

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An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis.
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2020-02-18 , DOI: 10.1016/j.chom.2020.01.008
Arthur S Kim ₁ , Ofer Zimmerman ₂ , Julie M Fox ₂ , Christopher A Nelson ₃ , Katherine Basore ₃ , Rong Zhang ₄ , Lorellin Durnell ₂ , Chandni Desai ₃ , Christopher Bullock ₃ , Sharon L Deem ₅ , Jonas Oppenheimer ₆ , Beth Shapiro ₇ , Ting Wang ₈ , Sara Cherry ₉ , Carolyn B Coyne ₁₀ , Scott A Handley ₃ , Michael J Landis ₁₁ , Daved H Fremont ₁₂ , Michael S Diamond ₁₃

Affiliation

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.
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; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Saint Louis Zoo Institute for Conservation Medicine, Saint Louis, MO 63110, USA.
Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Department Ecology and Evolutionary Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Department of Biology, Washington University, Saint Louis, MO 63110, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520, USA.
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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 Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Andrew M. and Jane M. Bursky the Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA.

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.

中文翻译：

Mxra8 受体结合位点的进化插入赋予对甲病毒感染和发病机制的抵抗力。

Alphaviruses 是新兴的蚊子传播的 RNA 病毒，其细胞趋向性和物种选择性知之甚少。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、绵羊和人类 Mxra8 的表达能够在细胞培养中感染甲病毒，但牛 Mxra8 却不能。牛 Mxra8 在其胞外域中编码一个 15 个氨基酸的插入，阻止 Mxra8 与 CHIKV 结合。在瘤牛、牦牛和已灭绝的野牛中存在相同的插入物。由于其他牛科动物谱系包含相关的 Mxra8 序列，这种插入可能发生在至少 500 万年前。去除牛亚科中的 Mxra8 插入可增强甲病毒结合和感染，同时将插入引入小鼠 Mxra8 会阻止 CHIKV 结合，防止细胞中多种甲病毒感染，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 感染的抵抗力的研究可以促进破坏 Mxra8 与甲病毒相互作用的对策。

更新日期：2020-02-20

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