M062 Is a Host Range Factor Essential for Myxoma Virus Pathogenesis and Functions as an Antagonist of Host SAMD9 in Human Cells
M062 Is a Host Range Factor Essential for Myxoma Virus Pathogenesis and Functions as an Antagonist of Host SAMD9 in Human Cells
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DOI：
10.1128/jvi.02243-10
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发表时间：
2011-04-01
影响因子：
5.4
通讯作者：
McFadden, Grant
中科院分区：
文献类型：
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作者：
Liu, Jia;Wennier, Sonia;McFadden, Grant
粘液瘤病毒(MYXV)M062R是正痘病毒宿主范围基因C7L家族的功能同源物。我们构建了靶向M062R-基因敲除-MYXV(vMyxM062-KO)，并对其体内外性质进行了研究。在欧洲兔中，vMyxM062-KO感染完全没有症状。幸存的兔子对随后的致死剂量的野生型MYXV没有获得完全的保护。我们还在各种培养细胞中寻找细胞趋向性缺陷。在所有被测试的兔细胞中，vMyxM062-KO进行流产感染，尽管它启动了病毒DNA复制。在许多但不是所有允许野生型MYXV的人类癌细胞中，vMyxM062-KO显示出严重的复制缺陷。我们将测试的人类细胞分为两组：(I)A型，支持野生型MYXV的生产性复制，但不能通过vMyxM062-KO产生显著水平的子代病毒；(Ii)B型，允许野生型MYXV和vMyxM062-KO感染。此外，利用蛋白质组学策略，我们确定包含9的不育α基序结构域(SAMD9)是M062在人类细胞中唯一的宿主结合伙伴。SAMD9是一种干扰素调节的细胞蛋白，与人类炎症疾病有关。值得注意的是，在A型人类癌细胞中敲除SAMD9导致了vMyxM062-KO感染的实质性挽救。总之，M062是一种新的宿主范围因子，它控制着MYXV在兔细胞和各种人类细胞中的高效复制。M062还与人类细胞中的SAMD9结合并拮抗，提示SAMD9是一种新的抗痘病毒的先天抗病毒因子。
Myxoma virus (MYXV) M062R is a functional homolog of the C7L family of host range genes from orthopoxviruses. We constructed a targeted M062R-knockout-MYXV (vMyxM062-KO) and characterized its properties in vitro and in vivo. In European rabbits, infection by vMyxM062-KO was completely asymptomatic. The surviving rabbits did not gain full protection against the subsequent lethal-dose challenge with wild-type MYXV. We also looked for cellular tropism defects in a variety of cultured cells. In all of the rabbit cells tested, vMyxM062-KO conducts an abortive infection, although it initiates viral DNA replication. In many, but not all, human cancer cells that are permissive for wild-type MYXV, vMyxM062-KO exhibited a profound replication defect. We categorized human cells tested into two groups: (i) type A, which support productive replication for wild-type MYXV but are unable to produce significant levels of progeny virus by vMyxM062-KO, and (ii) type B, which are permissive to infections by both wild-type MYXV and vMyxM062-KO. Furthermore, using proteomic strategies, we identified sterile alpha motif domain containing 9 (SAMD9), an interferon-regulated cellular protein implicated in human inflammatory disorders, as a unique host binding partner of M062 in human cells. Significantly, knocking down SAMD9 in type A human cancer cells led to a substantial rescue of vMyxM062-KO infection. In summary, M062 is a novel host range factor that controls productive MYXV replication in rabbit cells and in a wide variety of human cells. M062 also binds and antagonizes cellular SAMD9 in human cells, suggesting that SAMD9 is a novel innate antiviral factor against poxviruses.