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 Obsolete virus code: 58.1.5.0.001; superceded accession number: 58150001.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: none found.
Higher Order Taxa: Viruses: Group I dsDNA viruses, no RNA stage; Family: Poxviridae; SubFamily: Chordopoxvirinae; Leporipoxvirus; Genus: Leporipoxvirus, Species: Myxoma virus
Genus species Image: none available given copyright restrictions.
Description and significance: 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 just "Oryctolagus cuniculus".
When was your organism discovered/isolated?
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? Application to Biotechnology? What is its medical importance? What major research findings have been made with it? What do you find cool about your organism?
Myxoma virus may be an attractive oncolytic agent against human malignant glioma because of: 1) the nonpathogenic nature of myxoma virus outside of it 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 has been shown to selectively infect and kill human tumor cells, a unique capability that is linked to dysregulated intracellular signalling pathways found in the majority of human cancers.
myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.
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 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 susceptible to productive lethal infections by MV. All rhabdoid tumor cell lines tested in vitro were susceptible to productive lethal infections by MV. Intraturmoral injection of live MV dramatically reduced the size of s.c. rhabdoid tumor xenografts compared with control animals.
MV infects a wide range of human cancer cells in vitro, in a manner intricately linked to the cellular activation of Akt kinase. MV has also been successfully used for treating human glioma xenografts in immunodeficient mice. This study examines the effectiveness of MV in treating primary and metastatic mouse tumors in immunocompetent C57BL6 mice. We have found that several mouse tumor cell lines, including B16 melanomas, are permissive to MV infection. B16F10 cells were used for assessing MV replication and efficacy in syngeneic primary tumor and metastatic models in vivo. Multiple intratumoral injections of MV resulted in dramatic inhibition of tumor growth. Systemic administration of MV in a lung metastasis model with B16F10LacZ cells was dramatically effective in reducing lung tumor burden. Combination therapy of MV with rapamycin reduced both size and number of lung metastases.
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