Department of Medicine, Washington University School of Medicine, St. 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.
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Rep. 2019 Sep 3;28(10):2647-2658.e5. doi: 10.1016/j.celrep.2019.07.105.
Mxra8 is a recently described receptor for multiple alphaviruses, including Chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O'nyong nyong (ONNV) viruses. To determine its role in pathogenesis, we generated mice with mutant Mxra8 alleles: an 8-nucleotide deletion that produces a truncated, soluble form (Mxra8) and a 97-nucleotide deletion that abolishes Mxra8 expression (Mxra8). Mxra8 and Mxra8 fibroblasts show reduced CHIKV infection in culture, and Mxra8 and Mxra8 mice have decreased infection of musculoskeletal tissues with CHIKV, MAYV, RRV, or ONNV. Less foot swelling is observed in CHIKV-infected Mxra8 mutant mice, which correlated with fewer infiltrating neutrophils and cytokines. A recombinant E2-D71A CHIKV with diminished binding to Mxra8 is attenuated in vivo in wild-type mice. Ectopic Mxra8 expression is sufficient to enhance CHIKV infection and lethality in transgenic flies. These studies establish a role for Mxra8 in the pathogenesis of multiple alphaviruses and suggest that targeting this protein may mitigate disease in humans.
Mxra8 是一种最近被描述的多种甲病毒受体，包括基孔肯雅（CHIKV）、马亚罗（MAYV）、罗斯河（RRV）和奥尼永尼翁（ONNV）病毒。为了确定其在发病机制中的作用，我们生成了具有突变 Mxra8 等位基因的小鼠：一个 8 个核苷酸的缺失导致产生截断的可溶性形式（Mxra8），以及一个 97 个核苷酸的缺失导致 Mxra8 表达被废除（Mxra8）。Mxra8 和 Mxra8 成纤维细胞在培养中显示出对 CHIKV 感染的减少，而 Mxra8 和 Mxra8 小鼠的肌肉骨骼组织感染 CHIKV、MAYV、RRV 或 ONNV 的情况减少。在感染 CHIKV 的 Mxra8 突变小鼠中观察到较少的足部肿胀，这与浸润的中性粒细胞和细胞因子减少有关。与 Mxra8 结合减少的重组 E2-D71A CHIKV 在野生型小鼠中体内减毒。异位表达 Mxra8 足以增强转基因果蝇中的 CHIKV 感染和致死率。这些研究确立了 Mxra8 在多种甲病毒发病机制中的作用，并表明靶向该蛋白可能减轻人类的疾病。
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