Myxoma Virus

Ex. Myxoma virus in rabits

Characteristics of the symbiont/pathogen

Myxoma Virus (3).

The myxoma genome is 161.8-kb long consisting of 171 unique genes (1F) making up this large, linear double-stranded DNA virus. The myxoma virus has a brick shaped viron and replicates only within the cytoplasm of the host cell (1).This enveloped virus is a member of the Poxvirus family and is of the Leporipoxvirus genus (3). The myxoma virus genome has terminal inverted repeats and covalently closed hairpin ends. The genes near the termini are not necessary for replication but are important in the virus’ virulence in infected animals (2).

Characteristics of the host

The european rabbit (Oryctolagus cuniculus) is the host of the Myxoma virus (6).

The host of the myxoma virus is European rabbits (Oryctolagus cuniculus). In this specific host, the myxoma virus causes a deadly infection called myxomatosis. The myxoma virus can infect other types of rabbits (including the American rabbit, Oryctolagus cuniculus), but only causes myxomatosis in European rabbits (5). In Britain, the major vector is the rabbit flea, whereas in Australia, the vector is the mosquito (10). The virus causes a tumor at the infection site of the rabbits and causes swelling of the adjacent connective tissues. Secondary myxoma tumors are found on other areas of infected rabbits (5).

Host-Symbiont Interaction

The myxoma virus is a parasitic symbiont to European rabbits (17). The relationship between the European rabbit and the myxoma virus is important to microbiologists because it is one of the few natural infections in which virulence can be equated with lethality (7). The myxoma virus causes lethal myxomatosis in European rabbits, a disease which causes tumor-like lesions, suppresses the immune system of the rabbits, and leads to a secondary gram negative bacterial infection. This relationship results in death of the European rabbit host (8).

Molecular Insights into the Symbiosis

The myxoma virus has a M-T7 protein that is specific in that it specifically binds rabbit IFN-gamma. By doing this, the M-T7 protein inhibits a regulatory cytokine that controls the host’s immune response to viral infections. This makes the M-T7 protein a critical virulence factor in the progression of myxomatosis (9). The M130R protein and SERP1 gene are also important virulence factors. The M130R protein is necessary for complete and lethal development of the myxoma virus. Without the M130R protein, the host immune system is able to respond and control the lethal effects of the virus (14). The SERP1 gene interacts with cellular components involved in the regulation of inflammation. When this gene is absent the infection resolves more rapidly due to a more effective inflammatory reponse (15). There are also several ways that poxviruses increase the virus' ability to survive in the wild. These mechanisms can involve the interference with major histocompatibility complex antigen presentation, inhibition of apoptosis, disruption of complement cascade, and inhibition of cytokines (2). Specifically, the myxoma virus uses inhibition of apoptosis to increase the virus' ability to survive in the wild. This inhibition of apoptosis is accomplished through the M11L genes which extend the host range and increases myxoma survival in the wild (18).

Ecological and Evolutionary Aspects

The myxoma virus origionated in North and South America as it evolved in close association with Sylvilagus (the cottontail rabbit). However, after 1950, the disease began to be used as a way to control rabbit populations in Europe, Australia, and Chile. Many different strands of the myxoma virus exist with virulances ranging from 50-95%. The more virulent strands were used as a way to control rabbit populations in these countries between 1950 and 1960 (10).

As of 2006, the myxoma virus is endemic of North America, South America, Europe, and Australia. In Brazil and Uruguay, the myxoma virus was found in rabbits of the Sylvilagus genus, however in other countries of South America, such a Brazil, the myxoma virus is found primarily in the European rabbit. In North America, the myxoma virus is found in rabbits of the Sylvilagus genus. In Australia and Europe, the myxoma virus is predominately found in European rabbits (O. cuniculus) (10).

In places like Italy, rabbits can be vaccinated against the myxoma virus. It is accomplished by injecting rabbits with attenuated strains of Borghi or SG33 (16).

Recent Discoveries

The myxoma virus decreases the size of cancerous tumors. The closed squares represent cells that were treated with the myxoma virus and the closed diamonds represent cells that were not treated with the myxoma virus illustrating the trend that the myxoma virus decreases the size of cancerous tumors (11).

Current research is investigating the effect of the myxoma virus on cancerous tumors in mice. The myxoma virus was injected multiple times into cancerous tumors of mice. The viral injections resulted in a decreased size of the tumors (specifically B16F10 tumors). Additionally, systemic treatment of mice inhibited the development of lung metastasis. Mice were exposed to B16F10LacZ cells that cause lung metastasis and the mice that were treated with the myxoma virus did not develop observable tumors (11).

Other current research deals with the myxoma virus’ ability to kill most human malignant glioma cell lines. A single injection of the myxoma virus into the tumor dramatically increased the subject's median survival when compared to glioma tumors that were not treated with the myxoma virus. The median survival of myxoma treated subjects was 50.7 days compared to 47.3 days for the subjects that were not treated with myxoma virus. Additionally, 92% of the myxoma treated subjects were cured at the end of treatment and showed no remaining glioma tumors. This research also demonstrated that the myxoma virus is safe to administer to immunocompromised mice. It was found that the way in which the myxoma virus infected glioma cells was selective and this viral infection was long-lasting; lasting at least 42 days after initial infection (12).

A current study investigated reasons as to why the myxoma virus has not spread throughout North American species of rabbits. The Sylvilagus audubonii and Sylviagus nuttallii species were injected with the South American strain (Lu) and the Californian strain (MSW). After injection of the South American strain, neither species developed classical myxomatosis that can be observed in European rabbits. The Californian strain of the virus (MSW) replicated at the inoculation site, but did not show any signs of a disseminated infection. The virus did not reach transmissible titres in either of the species tested. This helps explain why the Californian myxoma virus has not yet spread throughout North American species (13).

References

(1.) Stanford, M., Werden, S., and McFadden, G. "Myxoma virus in the European rabbit: interactions between the virus and its susceptible host." Veterinary Research 2007; 38: 299-318.

(2.) Lalani, A., Graham, K., Mossman, K., Rajarathnam, K., Clark-Lewis, I., Kelvin, D., and McFadden, G. "The purified myxoma virus gamma interferon receptor homolog M-T7 interacts with the heparin-binding." Virology. 1997; 71(6):4356-4363.

(3.) Cameron, C., Hota-Mitchell, S., Chen, L., Barrett, J., Cao, J., Macaulay, C., Willer, D., Evans, D., and McFadden, D. "The Complete DNA Sequence of Myxoma Virus." Virology. 1999; 264(2): 298-318.

(4.) Padgett, B., Wright, M., Jayne, A., and Walker, D. "Electron microscope structure of myxoma virus and some reactivable derivatives." Journal of Bacteriology. 1964; 87(2): 454-460.

(5.) Mossman, K., Nation, P., Macen, J., Garbutt, M., Lucas, A., and McFadden, G. "Myxoma virus M-T7 secreted homolog of the interferon-y receptor, is a critical virulence factor for the development of myxomatosis in European rabbits." Virology. 1995; 215: 17-30.

(6.) Camus-Bouclainville, C., Gretillat, M., Py, R., Gelfi, J., and Bertagnoli, J. "Genome sequecne of SG33 strain and recombination between wild-type and vaccine myxoma virus." Emergine Infectious Diseases. 2011; 17(4): 633-638.

(7.) Fenner, F., and Marshall, I. "A comparison of the virulence for European rabbits (Oryctolagus cuniculus) of strains of myxoma virus recovered in the field in Australia, Europe, and America." Hygiene. 1957; 55(2): 149-190.

(8.) Opgenorth, A., Graham, K., Nation, N., Strayer, D., and McFadden, G. "Deletion analysis of two tenderly arranged virulence genes in myxoma virus, MilL and myxoma growth factor." Virology. 1992; 66(8): 4720-4731.

(9.) Upton, C., Mossman, K., and McFadden, G. "Encoding of a homolog of the IFN-gamma receptor by myxoma virus." Science. 1992; 20:1369-1372.

(10.) Fenner, F. and Chapple, P. "Evolutionary changes in myxoma virus in Britain." The Journal of Hygiene. 1965; 63: 175-185.

(11.) Stanford, M., Shaban, M., Barrett, J., Werden, S., Gilbert, P., Bondy-Denomy, J., MacKenzie, L., Grahm, K., Chambers, A., and McFadden, G. "Myxoma Virus Oncolysis of Primary an299-318d Metastatic B16F10 Mouse Tumors In Vivo." Molecular Therapy. 2007; 16: 52-59.

(12.) Lun, X., Yang, W., Alain, T., Shi, Z., Muzik, H., Barrett, J., McFadden, G., Bell, J., Hamilton, M., Senger, D., and Forsyth, P. "Myxoma Virus Is a Novel Oncolytic Virus with Significant Antitumor Activity against Experimental Human Gliomas." Cancer Research. 2005; 65: 9982-9992.

(13.) Silvers, L., Barnard, D., Knowlton, F., Inglis, B., Labudovic, A., Holland, M., Janssens, P., Van Leeuween, B., and Kerr, P. 2010. Host-specificity of myxoma virus: Pathogenesis of South American and North American strains of myxoma virus in two lagomorph species. Veterinary Microbiology 141: 289-300.

(14.) Barrett, J., Werden, S. , Wang, F., McKillop, W., Jimenez, J., Villeneuve, D., McFadden, G., and Dekaban, G. 2009. Myxoma virus M130R is a novel virulence factor required for lethal myxomatosis in rabbits. Virus Research 144: 258-265.

(15.) Macen, J., Upton, C., Nation, N., and McFadden, G. 1993. SERP1, a Serine Proteinase Inhibitor Encoded by Myxoma Virus, Is a Secreted Glycoprotein That Interferes with Inflammation. Virology 195: 348-363.

(16.) Cavadini, P., Barbieri, I., Lavazza, A., and Capucci, L. 2010. Molecular characterization of SG33 and Borghi vaccines used against myxomatosis. Vaccines 28: 5714-5420.

(17.) Bandyopadhyay, P. and Mandal, D. 2011. Advances in Parasitology: A Novel Approach Towards a Disease Free World. 22nd National Congress of Parasitology 1: 1-324.

(18.) Su, J., Wang, G., Barrett, J., Irvine, T., Gao, X., and McFadden, G. 2006. Myxoma virus M11L blocks apoptosis through inhibition of conformational activation of Bax at the mitochondria. J. Virol 80: 1140-51.

Edited by Darcy Paulus, student of Grace Lim-Fong