Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, 1600 SW Archer Rd., P.O. Box 100266, Gainesville, FL 32610, USA.
J Virol. 2011 Apr;85(7):3270-82. doi: 10.1128/JVI.02243-10. Epub 2011 Jan 19.
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 α 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.
粘液瘤病毒 (MYXV) M062R 是一种功能同源物，与正痘病毒的 C7L 家族的宿主范围基因有关。我们构建了一种靶向 M062R 敲除-MYXV（vMyxM062-KO），并在体外和体内对其特性进行了表征。在欧洲兔中，vMyxM062-KO 的感染完全无症状。幸存的兔子没有完全获得针对野生型 MYXV 的随后致死剂量挑战的完全保护。我们还在各种培养细胞中寻找细胞嗜性缺陷。在所有测试的兔细胞中，尽管 vMyxM062-KO 启动了病毒 DNA 复制，但它仍进行了流产感染。在许多但不是所有允许野生型 MYXV 感染的人类癌细胞中，vMyxM062-KO 表现出明显的复制缺陷。我们将测试的人类细胞分为两类：（i）A型，支持野生型 MYXV 的有效复制，但不能由 vMyxM062-KO 产生大量子代病毒；（ii）B 型，允许野生型 MYXV 和 vMyxM062-KO 感染。此外，使用蛋白质组学策略，我们鉴定出包含 sterile α motif 结构域的 9 号（SAMD9），一种与人类炎症性疾病有关的干扰素调节的细胞蛋白，作为人类细胞中 M062 的独特宿主结合伴侣。重要的是，在 A 型人类癌细胞中敲低 SAMD9 可导致 vMyxM062-KO 感染的显著挽救。总之，M062 是一种新型宿主范围因子，可控制兔细胞和各种人类细胞中有效的 MYXV 复制。M062 还在人类细胞中结合并拮抗细胞 SAMD9，表明 SAMD9 是一种针对痘病毒的新型先天抗病毒因子。
