M062 is a host range factor essential for myxoma virus pathogenesis and functions as an antagonist of host SAMD9 in human cells.
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.
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, 1600 SW Archer Rd., P.O. Box 100266, Gainesville, FL 32610, USA.
Jia
J
Liu
Sonia
S
Wennier
Leiliang
L
Zhang
Grant
G
McFadden
D000818:Animals; D045744:Cell Line, Tumor; D017353:Gene Deletion; D058507:Host Specificity; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009233:Myxoma virus / Q000472:pathogenicity*; D011213:Poxviridae Infections / Q000401:mortality / Q000821:virology; D011506:Proteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D016019:Survival Analysis; D014412:Tumor Virus Infections / Q000401:mortality / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D047908:Intracellular Signaling Peptides and Proteins; C000619471:M062 protein, myxoma virus; D011506:Proteins; C514443:SAMD9 protein, human; D014764:Viral Proteins; D037521:Virulence Factors
J Virol. 2009 Jun;83(11):5933-8
19279088
Microbes Infect. 2010 Dec;12(14-15):1144-52
20832500
Cancer Res. 2005 Nov 1;65(21):9982-9990
16267023
J Invest Dermatol. 2008 Jun;128(6):1423-9
18094730
Am J Hum Genet. 2006 Oct;79(4):759-64
16960814
J Exp Med. 2008 Dec 22;205(13):2995-3006
19047436
J Virol. 1995 Sep;69(9):5243-51
7636966
J Gen Virol. 2010 Feb;91(Pt 2):470-82
19846675
J Neurovirol. 2007 Dec;13(6):549-60
18097886
BMC Genomics. 2007 Apr 03;8:92
17407603
J Virol. 2009 Oct;83(20):10627-36
19656868
Virology. 2007 Apr 25;361(1):123-32
17184804
Curr Protoc Microbiol. 2010 May;Chapter 14:Unit 14A.1
20440681
Virology. 1996 Aug 1;222(1):75-86
8806489
Cell Microbiol. 2004 Aug;6(8):695-705
15236637
Vet Res. 2008 Nov-Dec;39(6):60
18778680
J Virol. 2008 Aug;82(15):7467-74
18508896
J Invest Dermatol. 2011 Mar;131(3):662-9
21160498
Biochem J. 2000 Apr 15;347(Pt 2):375-82
10749666
Virology. 2008 Mar 15;372(2):372-83
18054061
BMC Mol Biol. 2006 Dec 06;7:46
17150110
Int J Cancer. 2010 Apr 15;126(8):1982-1991
19830690
Eur J Pediatr. 1988 Feb;147(2):128-32
3366131