Institute of Virology, Medical Center-University of Freiburg, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
PLoS Pathog. 2020 Nov 16;16(11):e1009038. doi: 10.1371/journal.ppat.1009038. eCollection 2020 Nov.
Infections with emerging and re-emerging arboviruses are of increasing concern for global health. Tick-transmitted RNA viruses of the genus Thogotovirus in the Orthomyxoviridae family have considerable zoonotic potential, as indicated by the recent emergence of Bourbon virus in the USA. To successfully infect humans, arboviruses have to escape the restrictive power of the interferon defense system. This is exemplified by the high sensitivity of thogotoviruses to the antiviral action of the interferon-induced myxovirus resistance protein A (MxA) that inhibits the polymerase activity of incoming viral ribonucleoprotein complexes. Acquiring resistance to human MxA would be expected to enhance the zoonotic potential of these pathogens. Therefore, we screened a panel of 10 different thogotovirus isolates obtained from various parts of the world for their sensitivity to MxA. A single isolate from Nigeria, Jos virus, showed resistance to the antiviral action of MxA in cell culture and in MxA-transgenic mice, whereas the prototypic Sicilian isolate SiAr126 was fully MxA-sensitive. Further analysis identified two amino acid substitutions (G327R and R328V) in the viral nucleoprotein as determinants for MxA resistance. Importantly, when introduced into SiAr126, the R328V mutation resulted in complete MxA escape of the recombinant virus, without causing any viral fitness loss. The escape mutation abolished viral nucleoprotein recognition by MxA and allowed unhindered viral growth in MxA-expressing cells and in MxA-transgenic mice. These findings demonstrate that thogotoviruses can overcome the species barrier by escaping MxA restriction and reveal that these tick-transmitted viruses may have a greater zoonotic potential than previously suspected.
新兴和再现虫媒病毒感染对全球健康的关注日益增加。正粘病毒科的 Thogotovirus 属的蜱传 RNA 病毒具有相当大的人畜共患病潜力，最近在美国出现的 Bourbon 病毒就是证明。为了成功感染人类，虫媒病毒必须逃脱干扰素防御系统的限制作用。这可以通过 Thogotovirus 对干扰素诱导的粘病毒抗性蛋白 A（MxA）的抗病毒作用的高度敏感性来证明，该蛋白抑制进入的病毒核糖核蛋白复合物的聚合酶活性。预计对人 MxA 的抗性获得将增强这些病原体的人畜共患病潜力。因此，我们筛选了来自世界各地的 10 种不同的 Thogotovirus 分离株，以确定它们对 MxA 的敏感性。来自尼日利亚 Jos 病毒的单个分离株在细胞培养和 MxA 转基因小鼠中显示出对 MxA 抗病毒作用的抗性，而原型西西里岛分离株 SiAr126 则完全对 MxA 敏感。进一步的分析确定了病毒核蛋白中的两个氨基酸取代（G327R 和 R328V）是 MxA 抗性的决定因素。重要的是，当引入 SiAr126 时，R328V 突变导致重组病毒完全逃避 MxA，而不会导致任何病毒适应性损失。逃逸突变消除了 MxA 对病毒核蛋白的识别，并允许在表达 MxA 的细胞和 MxA 转基因小鼠中不受阻碍地进行病毒生长。这些发现表明，Thogotovirus 可以通过逃避 MxA 限制来克服种间屏障，并表明这些蜱传病毒可能比先前怀疑的具有更大的人畜共患病潜力。
