Amino Acid Residue at Position 79 of Marburg Virus VP40 Confers Interferon Antagonism in Mouse Cells
Amino Acid Residue at Position 79 of Marburg Virus VP40 Confers Interferon Antagonism in Mouse Cells
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DOI：
10.1093/infdis/jiv010
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发表时间：
2015-10-01
影响因子：
6.4
通讯作者：
Basler, Christopher F.
中科院分区：
文献类型：
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作者：
Feagins, Alicia R.;Basler, Christopher F.
马尔堡病毒（MARV）在人类和非人灵长类动物中引起高度致死性感染。小鼠一般不容易感染MARV;然而，如果该菌株首先通过连续传代适应小鼠，则它能够在该动物中引起疾病。先前的一项研究将小鼠适应过程中MARV毒株（称为Ravn病毒（RAVV））VP 40基因的变化与小鼠细胞系中抑制干扰素（IFN）信号传导的能力增加相关联。属于与RAVV不同的系统发育进化枝的MARV毒株Ci 67也已适应小鼠，并且在此过程中Ci 67 VP 40获得了与RAVV VP 40不同的遗传变化集合。在这里，我们证明了小鼠适应的Ci 67 VP 40更有力地拮抗IFN-α/β诱导的STAT 1和STAT 2酪氨酸磷酸化，基因表达和抗病毒活性在小鼠和人类细胞系中，与亲本Ci 67 VP 40相比。Ci 67 VP 40也被证明靶向激酶Jak 1的活化。发现VP 40残基79处的单一变化足以增加VP 40 IFN拮抗作用。这些数据表明，VP 40 IFN-拮抗剂活性在小鼠MARV发病机制中起关键作用。
Marburg viruses (MARVs) cause highly lethal infections in humans and nonhuman primates. Mice are not generally susceptible to MARV infection; however, if the strain is first adapted to mice through serial passaging, it becomes able to cause disease in this animal. A previous study correlated changes accrued during mouse adaptation in the VP40 gene of a MARV strain known as Ravn virus (RAVV) with an increased capacity to inhibit interferon (IFN) signaling in mouse cell lines. The MARV strain Ci67, which belongs to a different phylogenetic clade than RAVV, has also been adapted to mice and in the process the Ci67 VP40 acquired a different collection of genetic changes than did RAVV VP40. Here, we demonstrate that the mouse-adapted Ci67 VP40 more potently antagonizes IFN-alpha/beta-induced STAT1 and STAT2 tyrosine phosphorylation, gene expression, and antiviral activity in both mouse and human cell lines, compared with the parental Ci67 VP40. Ci67 VP40 is also demonstrated to target the activation of kinase Jak1. A single change at VP40 residue 79 was found to be sufficient for the increased VP40 IFN antagonism. These data argue that VP40 IFN-antagonist activity plays a key role in MARV pathogenesis in mice.