Myxomatosis

VIRUSES POXVIRUSES

A European Rabbit afflicted by Myxomatosis in Shropshire, England. Courtesy of WikiMedia

Antigenicity

• Myxomatosis is enzootic in rabbits of the genus Sylvilagus in both South and North America and in wild rabbits of the genus Oryctolagus in South America, Europe, and Australia
• Following introduction into Europe and Australia, genetic modification of the myxoma virus produced markedly attenuated strains that replaced the virulent virus as the dominant virus strain

Morphology

• Several proteins encoded by the virus are immunosubversive in that they mimic host ligands or regulators (virokines) or are homologues of cellular cytokine receptors (viroceptors)

Hosts

• Rabbits

Pathogenesis

• Infects several cell types including mucosal cells, lymphocytes, and fibroblasts
• In addition to primary and secondary tumor development, there is severe immunosuppression leading to overwhelming infections by opportunistic gram-negative bacteria (esp. conjunctiva and nasal passages)
• Virus multiplication and tumor-like lesions occur initially at the site of intradermal inoculation
• This is followed by spread to regional lymph nodes and cell-associated viremia, with generalization to the skin and internal organs
• Gelatinous proliferative nodules all over body, especially at orifices (eyes, anus, nose)
• Rabbit dies within 12 days, if not killed by predators

In more detail

• Virulent strains of MYX and MRV secrete a T2 gene product with significant homology to the T2 protein secreted by Shope fibroma virus. This protein acts as a receptor for TNFα and TNFβ. TNF is active in killing virus infected and tumor cells. Cytotoxicity is correlated with the induction of toxic superoxide radicals. The T2 gene product enhances viral virulence by interfering with TNF-dependent immune response pathways of the host.
• Myxoma virus and MRV have also been shown to compromise cell-mediated immunity by inducing a loss of class I MHC antigens from the surface of infected cells. MHC class I-restricted cytotoxic T lymphocytes play a major role in clearing poxvirus infections from susceptible animal hosts, and are an important factor in limiting virus spread within the host. Class I molecules are present on all nucleated cells and platelets. Cytotoxic T cells (CD8+) recognize intracellular viral antigen in association with class I MHC glycoproteins on the cell surface. MYX and MRV infection results in a specific, rapid decrease in detectable surface class I epitopes. It has been suggested that a late viral gene product may interact with the class I complex to either physically sequester the complex away from the cell surface and inhibit its recycling to the surface, or induce a conformational change in the complex rendering it unrecognizable by cytotoxic T lymphocytes.
• Myxoma growth factor (MGF) and a gene product designated M11L are also associated with MYX virulence. MGF and M11L deleted mutants are markedly attenuated, capable of inducing only benign localized nodules that regress spontaneously, similar to lesions induced by Shope fibroma virus. MGF has significant sequence homology with epidermal growth factor and transforming growth factor β. It has been postulated that the presence of EGF/TGFβ-like growth factors in tumorigenic poxviruses affects the growth and progression of poxvirus-infected cells.
• Another myxoma virus virulence factor designated MYXOMA SERPIN 1 (SERP 1) has significant sequence homology with members of the family of serine proteases inhibitors (serpins). The exact role of SERP 1 is unknown but it may theoretically affect antigen presentation by interfering with viral protein degradation, or might reduce cytoxic T cell killing mediated by serine proteases in the effector cell.
• Rabbit poxvirus gene sequences coding for products related to the C4 and C5 components of the complement cascade have been identified. It is postulated that complement-like viral protein products may block the activation or action of complement. The virulence factor T7 is an IFNγ receptor homologue.

Clinical Signs

• Clinical disease varies with virus strain and host species.
  • Sylvilagus species are relatively resistant, and are probably the natural host of the virus. In Sylvilagus species, infection usually results only in the development of skin tumors at the site of inoculation. The tumors appear 4-8 days after exposure and persist for up to 40 days. Very young rabbits may succumb to generalized disease.
  • Lepus species (hares) are highly resistant. Occasional individuals develop mild to severe generalized myxomatosis.
  • In the European rabbit (Oryctolagus cuniculus), infection with virulent virus (South American or California strains) results in severe disease with up to a 99% case fatality rate.
    • Initial signs include edema of the eyelids accompanied by inflammation and edema around the anal, genital, oral, and nasal orifices.
    • Edema of the head and ears, drooping ears, and bacterial infections resulting in mucopurulent conjunctivitis and pneumonia are seen.
    • The primary tumor may be evident by 3-4 days after infection. Generalized tumors develop by 6-7 days after infection.
    • Subcutaneous swellings become mucoid, gelatinous masses (hence the name myxomatosis).
    • More chronic wart-like nodules appear, especially at mucocutaneous borders, after 10-14 days.
    • Death (8-15 days post infection) is usually preceded by labored breathing and convulsions.

Pathology

• The most prominent gross lesions in European rabbits with myxomatosis are the skin tumors and the pronounced cutaneous and subcutaneous edema, particularly in the area of the face and around body orifices.
• Skin hemorrhages, subserosal petechiae and ecchymoses may be observed in the stomach and intestines. Subepicardial and subendocardial hemorrhages may also occur.
• Adult rabbits of the genus Sylvilagus usually develop localized skin tumors resembling the fibromas produced in European rabbits by Shope fibroma virus.
• Hares or young Sylvilagus rabbits may develop fibromatous to myxomatous nodules, however, lesions are usually mild and localized.

Histopathology

• The lesions are proliferative to degenerative, depending on the virus strain.
• The skin tumors result from proliferation of undifferentiated mesenchymal cells which become large stellate cells (myxoma cells). These cells may contain intracytoplasmic eosinophilic inclusions. These cells lie in a homogeneous matrix of mucinous material interspersed with capillaries and inflammatory cells. Endothelial proliferation with narrowing of the lumen and extrusion of stellate "myxoma" cells has been described.
• Epithelial cells overlying the tumor may show hyperplasia or degeneration, or may appear normal. Epithelial proliferation is characterized by ballooning of cells in the stratum granulosum and hyperkeratosis. Epithelial vesiculation progresses to crust formation. Large, eosinophilic, intracytoplasmic inclusions are especially prominent in the stratum spinosum. Lesions in other organs include cellular proliferation of alveolar epithelium and the reticulum cells of lymph nodes and spleen. Focal hemorrhage may be present in skin, kidneys, lymph nodes, testes, heart, stomach, and intestinal walls. Myxoma cells may be present in lymph nodes, bone marrow, uterus, ovaries, testes, and lungs.

Epidemiology

• Highly contagious and transmitted by direct or indirect contact with ocular or skin discharges or by mechanical vectors
• Mosquitoes act as mechanical vectors
• High ambient environmental temperatures are associated with increased survival of infected animals

Differentials

• Shope fibroma virus
  • Localised benign tumours that spontaneously regress in adult immunocompetent rabbits
• Malignant rabbit fibroma virus
  • MRV is a recombinant between Myxoma virus and Shope fibroma virus.
  • Causes a lethal disease with numerous primary and secondary tumours and immunosuppression.

Control

• Attenuated vaccines are used for farmed and pet rabbits
• Wild suspect animals should be culled