Myxoma virus

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Classification:

ICTVdB Virus Code: 00.058.1.05.001. Virus accession number: 58105001. Obsolete virus code: 58.1.5.0.001; superceded accession number: 58150001. NCBI Taxon Identifier NCBI Taxonomy ID: 10273. Type of the genus: 00.058.1.05. [1]poripoxvirus]|Leporipoxvirus subfamily 00.058.1. [Chordopoxvirinae]|[2] in the family 00.058. Poxviridae.]

Image:

Higher Order Taxa:

Viruses: Group I dsDNA viruses, no RNA stage; Family: Poxviridae; SubFamily: Chordopoxvirinae; Genus: Leporipoxvirus,

Species:

Myxoma virus

Genus Species: Leporipoxvirus:

Description and significance:

Myxoma virus is a member of the Poxviridae family. It causes a benign infection rabbits of the Sylvilagus genus, but induces a fatal disease known as myxomatosis in the European rabbit, Oryctalagus cuniculus. Myxoma virions have two complex structures having either an envelope or no envelope, a surface membrane, a core, and lateral bodies. The envelope contains host-derived lipids and self-synthesized glycolipids. In the course of its life cycle, these virions produce both extracellular and intracellular particles. They can have two phenotypes and may be enveloped during their extracellular phase. The extracellular virions initiate viral infection. Myxoma virions may be segregated within *non-occluded inclusion bodies. Typically they contain one enveloped nucleocapsid and are slightly pleomorphic, brick–shaped, and measure approximately 250 nm in diameter, 250–300 nm in length, and 200 nm in height. The core is biconcave with two lateral bodies, nested between either the core membrane or the surface membrane. They mature by budding through the membrane of the host cell. The Myxoma virus was important enough to have its genome sequenced is because it encodes multiple gene products designed to circumvent the host's cellular immune response to the viral infection, thereby inducing extensive immunosuppression in infected rabbits.

Natural Host:

Domain Eucarya, Kingdom Animalia, Phylum Chordata, Subphylum Vertebrata, Class Mammalia, Order Lagomorphia, purportedly only in Oryctolagus cuniculus, Lepus Europaeus, S. Bachmani, and S. floridanus.

When was your organism discovered?

Myxoma virus was first discovered in imported European rabbits by Sanarelli in Uruguay in 1896 at the Institute of Hygiene in Montivideo.

How and where it was isolated:

The Lausanne strain of the virus was isolated by a team of Canadian scientists at the Department of Microbiology, The University of Western Ontario, London, Ontario, Canada. However, only a partial sequencing of the California MSW strain was achieved by a team associated with School of Biochemistry and Molecular Biology, Faculty of Science, Australian National University, Canberra, Australia. There they cloned EcoRI and SalI restriction fragments of viral DNA and sequenced the ends.

Genome structure:

Describe the size and content of the genome. The genome is not segmented and consists of a single molecule of linear double-stranded DNA. Sequence has the accession number [M93049]. The genome is 161,773 nucleotides long with a central region consisting of highly conserved enzymatic and structural genes that are required for essential viral functions. At both ends however are terminal sequences which include two copies of the 12 genes that map within the 11.5-kb terminal inverted repeats that are cross-linked hairpin ends forming one continuous polynucleotide chain. These sequences encode nonessential factors which affect the host's response to infection. These factors include serine proteinase inhibitors, such as SERP1, Serp2, and Serp3, and a scrapin. They are responsible for major histo-compatibility complex class I down regulation. Additionally, the genome has a guanine + cytosine content of approximately 40%. [Cheryl Cameron et al. "The Complete DNA Sequence of Myxoma Virus." Virology, Volume 264, Issue 2, 25 November 1999, Pages 298-318].

Interesting Features:

Myxoma virus subverts the host immune response using two distinct viral mechanisms delivered by viral proteins. First the virus produces virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These act to block extracellular immune signals thereby providing effective clearance and producing a virus friendly environment. Secondly, the virus uses intracellular viral proteins to retard the innate antiviral responses such as apoptosis, and to thwart an infected cell's mechanisms to communicate with its immune system. Additionally, the myxoma virus gene expresses a five-membrane spanning cell surface protein that has amino acid homology to cellular CD47 proteins. CD47 is associated with leukocyte adhesion, motility, activation, and phagocytosis. M128L is necessary for the production of a lethal infection in susceptible rabbits. However it is not essential for the dissemination of virus within the host. The M128L protein is a novel CD47-like immunomodulatory gene of myxoma virus required for full pathogenesis of the virus.

How does this organism cause disease?

Myxoma virus (MV) is a poxvirus and a prototypical member of the Leporipoxvirus genus. It is the causative agent of myxomatosis, a lethal and severely deblilitating disease of European rabbits (Oryctolagus cuniculus). The disease is characterized by profound systemic cellular immunosuppression and a high rate of mortality. The myxoma virus encodes multiple proteins capable of downregulating the host innate and acquired immune responses. Other virus-encoded proteins enable replication in host lymphocytes and monocytes, for example, by inhibiting apoptosis. Specifically, Myxoma virus (MYX) prevents apoptosis in RK-13 cells and forms thick dermal lesions with 100% mortality in rabbits. MYX encodes the virulence factor SERP2, a serine proteinase inhibitor (serpin). Virulence may instead depend on inhibition of proinflammatory proteinases by SERP2. Nonetheless, despite the increasingly detailed molecular knowledge of myxoma virus, relatively little is known about the dynamics of the interaction of the virus with the integrated host-immune system during infection

What makes it biologically interesting?

Its application to Biotechnology, its medical importance, major research findings made with it, what's cool about myxoma virus as an organism:

• Myxoma virus has potential as an attractive oncolytic agent against human malignant glioma because of: 1) the nonpathogenic nature of myxoma virus outside of its host, 2) its capacity to be genetically modified, 3) its ability to produce a long-lived infection in human tumor cells, and 4) the lack of preexisting antibodies in the human population.

• Myxoma virus selectively infects and kills human tumor cells. This capability is linked to dysregulated intracellular signalling pathways found in the majority of human cancers.

• Myxoma virus appears to be an effective oncolytic agent against medulloblastoma. In fact, whether used alone or in combination with rapamycin, myxoma virus was found to be effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine out of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection. Additionally, it was found that the oncolytic potential myxoma virus was enhanced by combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway. Apparently, the susceptibility of human cancer cells to be infected and killed by an oncolytic poxvirus, myxoma virus (MV), is related to the basal level of endogenous phosphorylated Akt.

• All rhabdoid tumor cell lines tested in vitro were found to be susceptible to lethal infections by myxoma virus. Intraturmoral injection of live MV dramatically reduced the size of s.c. rhabdoid tumor xenografts compared with control animals.

• Myxoma virus has also been successfully used for treating human glioma xenografts in immunodeficient mice. Several mouse tumor cell lines, including B16 melanomas, are permissive to MV infection. Multiple intratumoral injections of MV resulted in dramatic inhibition of tumor growth, with systemic administration of MV in a lung metastasis model with B16F10LacZ cells dramatically reducing lung tumors.

Current Research:

Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo Marianne M Stanford, Mae Shaban, John W Barrett, Steven J Werden, Philippe-Alexandre Gilbert, Joe Bondy-Denomy, Lisa MacKenzie, Kevin C Graham, Ann F Chambers, and Grant McFadden Molecular Therapy (2008), Jan. 16(1):52–59.

This paper investigates the effectiveness of myxoma virus (MV) in treating primary and metastatic mouse tumors in immunocompetent C57BL6 mice. The authors found several mouse tumor cell lines, including B16 melanomas, to be permissive to MV infection. They used B16F10 cells to assess MV replication and efficacy in genetically similar primary tumor and metastatic models in vivo. Multiple intratumoral injections of MV caused substantial inhibition of tumor growth. Moreover, systemic administration of MV in a lung metastasis model with B16F10LacZ cells dramatically reduced lung tumors. Of particular note, a combination therapy of MV with rapamycin reduced both the size and number of lung metastases, as well as the induced antiviral neutralizing antibody titres. This study demonstrates that MV is capable of targeting and destroying tumors while causing no significant disease or collateral tissue infection in an immunocompetent host. Moreover when MV is combined rapamycin, the potential of MV is significant oncolytic cancer therapy.

Oncolytic efficacy of recombinant vesicular stomatitis virus and myxoma virus in experimental models of rhabdoid tumors. Wu Y, Lun X, Zhou H, Wang L, Sun B, Bell JC, Barrett JW, McFadden G, Biegel JA, Senger DL, Forsyth PA.Authors' Affiliations: Departments of Oncology, Clinical Neurosciences, and Biochemistry and Molecular Biology, University of Calgary, the Tom Baker Cancer Centre, and the Clark H. Smith Brain Tumour Research Centre, Calgary, Alberta, Canada. Clinical Cancer Research, 2008 Feb 15;14(4):1218-27.

This paper investigates the therapeutic potential of two oncolytic viruses, myxoma virus (MV) and an attenuated vesicular stomatitis virus (VSV(DeltaM51)) in models of human rhabdoid tumor. Rhabdoid tumors are highly aggressive pediatric tumors that are typically unsusceptible to treatment. In this experiment, four human rhabdoid tumor cell lines were cultured in vitro and treated with live or inactivated control virus. At various times after infection, the cytopathic effect, the viral gene expression, the infectious viral titers, and cell viability were measured. However, to gain insight into viral oncolysis in vivo, human rhabdoid tumor cells were implanted subcutaneously or intracranially in CD-1 nude mice, which were then treated with intratumoral or i.v. injections of live or UV-inactivated virus. In terms of results: 1) all in vitro rhabdoid tumor cell lines were susceptible to lethal infections by MV and VSV(DeltaM51); and 2)Intratumoral injection of live MV or VSV(DeltaM51) reduced the size of s.c. rhabdoid tumor xenografts "dramatically" when compared with control animals. Consequently, these results indicate that VSV(DeltaM51) and MV have potential as novel therapies against human rhabdoid tumor.

Oncolytic Virotherapy Synergism with Signaling Inhibitors: Rapamycin Increases Myxoma Virus Tropism for Human Tumor Cells Marianne M. Stanford, John W. Barrett, Steven H. Nazarian, Steven Werden, and Grant McFadden* Biotherapeutics Research Group, Robarts Research Institute, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G 2V4, Canada

• Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Western Ontario, Siebens-Drake Building, Rm. 126, London, Ontario N6G 2V4, Canada.

Journal of Virology, 2007 February; 81(3): 1251–1260.

Myxoma virus is a rabbit-specific poxvirus pathogen that also exhibits a unique tropism for human tumor cells and is dramatically oncolytic for human cancer xenografts. Most tumor cell lines tested are permissive for myxoma infection in a fashion intimately tied to the activation state of Akt kinase. A host range factor of myxoma virus, M-T5, directly interacts with Akt and mediates myxoma virus tumor cell tropism. mTOR is a regulator of cell growth and metabolism downstream of Akt and is specifically inhibited by rapamycin. We report that treatment of nonpermissive human tumor cell lines, which normally restrict myxoma virus replication, with rapamycin dramatically increased virus tropism and spread in vitro. This increased myxoma replication is concomitant with global effects on mTOR signaling, specifically, an increase in Akt kinase. In contrast to the effects on human cancer cells, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with constitutively active Akt. This indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to one that is optimal for productive virus replication and suggests the possibility of a potentially therapeutic synergism between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.

References:

• Fenner, F. (2000). Adventures with poxviruses of vertebrates. FEMS Microbiol Rev 24: 123–133.
• Stanford, MM, Werden, SJ and McFadden, G. (2007). Myxoma virus in the European rabbit: interactions between the virus and its susceptible host. Vet Res 38: 299–318
• Stanford, MM, Barrett, JW, Nazarian, SH, Werden, S and McFadden, G. (2007). Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells. J Virol 81: 1251–1260.
• Lun, X, Yang, W, Alain, T, Shi, ZQ, Muzik, H, Barrett, JW et al.(2005). Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas. Cancer Res 65: 9982–9990.
• Sypula, J, Wang, F, Ma, Y, Bell, JC and McFadden, G. (2004). Myxoma virus tropism in human tumor cells. Gene Ther Mol Biol 8: 108–114.
• Wang, G, Barrett, JW, Stanford, M, Werden, SJ, Johnston, JB, Gao, X et al.(2006). Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. Proc Natl Acad Sci USA 103: 4640–4645.
• Barrett, JW, Sypula, J, Wang, F, Alston, LR, Shao, Z, Gao, X et al.(2007). M135R is a novel cell surface virulence factor of myxoma virus. J Virol 81: 106–114.
• Cameron, C, Hota-Mitchell, S, Chen, L, Barrett, J, Cao, JX, Macaulay, C et al. (1999). The complete DNA sequence of myxoma virus. Virology 264: 298–318.
• Lun, XQ, Zhou, H, Alain, T, Sun, B, Wang, L, Barrett, JW et al.(2007). Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res 67: 8818–8827.