Difference between revisions of "Myxomatosis"

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Also known as '''''Rabbit Pox
 
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[[Image:Myxomatosis_rabbit_logo.jpg|200px|right|thumb|A European Rabbit afflicted by Myxomatosis Source: Wikimedia Commons; Author: Chris Bayley, 2007]]
 
  
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==Introduction==
+
[[Image:MyxoRabbit.JPG|200px|right|thumb|A European Rabbit afflicted by Myxomatosis in Shropshire, England.  Courtesy of WikiMedia]]
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Myxomatosis is a highly contagious viral condition of rabbits caused by the myxoma virus, a member of the poxvirus group. It was first recognised in the UK in 1953 after it crossed the channel from France where it was illegally introduced in 1952. It is carried mainly by arthropods, particularly the rabbit flea, ''Spilopsyllus cuniculi''. The disease is also transmitted by direct or indirect contact with ocular or skin discharges or by mechanical vectors. The disease is characterised by subcutaneous mucinous lesions and nodular tumours and is associated with a high mortality rate.
+
====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
  
−
Myxomatosis is enzootic in cottontail 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. All other animals are resistant to the disease. 
+
====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)
  
−
==Pathogenesis==
 
−
The myxoma virus infects several cell types including mucosal cells, lymphocytes and fibroblasts. In addition to primary and secondary tumour development, there is severe immunosuppression leading to overwhelming infections by opportunistic gram-negative bacteria particularly affecting the conjunctiva and nasal passages.
 
  
−
Virus multiplication and tumour-like lesions occur initially at the site of intradermal inoculation. This is followed by spread to regional lymph nodes and cell-associated viraemia, with generalization to the skin and internal organs. Gelatinous proliferative nodules develop all over the body, especially at orifices such as the eyes, anus, nose. There are three known forms of disease manifestation:
+
====Hosts====
−
*'''Acute Form''': this becomes apparent three days after experimental infection: oedema of the head, eyelids and genitals, followed by the appearance of myxomes. This form is usually fatal and death occurs wihtin 14 days (Okerman 1994).
+
*Rabbits
−
*'''The chronic, nodular form''' shows oedematous swellings called pseudotumours which develop after 10-15 days on the ears, nose and paws and is not so fatal (<50%) but mean survival time is 40 days (Okerman 1994). Lesions develop into hard scabs which heal into scars and sometimes can even lead to holes “punched” through the pinnae. This is the form that occurs in vaccinated animals may be worth treating in pet rabbits – oxytetracycline (Engemycin 5%®; Intervet) SC q 72hrs, good feeding and prokinetics if the gastrointestinal system seems compromised.
 
−
*'''A specialised form''' is seen in Angoras which have been vaccinated and then depilated: Lesions can be found on the torso only in animals with waning immunity after vaccination  and are considered to be a type IV hypersensitivity reaction (Ganiere et al 1990).
 
  
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==Epidemiology==
 
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The disease is transmitted by both direct and indirect means (Okerman 1994), the former principally involving contact with infected wild rabbits; the latter, with arthropod vectors, including fleas, lice and mosquitoes, although (Gaguere 1995) implied that the mosquito is the only vector worth considering. The incubation period of the virus is two to eight days, and the duration of illness is usually from eleven to eighteen days. Pyrexia (42ºC) is a feature of the disease at or around the second day. Death is inevitable and is usually due to secondary infection with ''Pasteurella'' spp (Harkness and Wagner 1989) which is also why some cases seem to respond initially to antibiosis.
 
  
−
==Clinical signs==
+
====Pathogenesis====
−
The clinical disease varies with the virus strain and host species. Lepus species (hares are highly resistant; occasional individuals develop mild to severe generalized myxomatosis. Sylvilagus species are relatively resistant and are probably the natural host of the virus. In this species, infection usually results in the development of skin tumours at the site of innoculation.  The tumours appear 4-8 days after exposure and persist for up to 40 days.
+
*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 the European rabbit (Oryctolagus cuniculus), infection with a virulent virus (i.e. the South American or California strains) results in severe disease with up to a 99% case fatality rate. Initial signs include oedema of the eyelids accompanied by inflammation and oedema of the anal, genital, oral and nasal orifices.  Oedema of the head and ears, drooping ears and bacterial infections resulting in mucopurulent conjunctivitis and pneumonia are seen. Severe pyrexia is frequently reported.  Death (8-15 days post infection) is usually preceded by dyspnoea and seizures.  The mortality rate is affected by environmental temperature, with the disease being more lethal at low temperatures.
+
=====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.
  
−
==Pathology==
+
=====Clinical Signs=====
−
The most prominent gross lesions in European rabbits with myxomatosis are the skin tumours and the pronounced cutaneous and subcutaneous oedema,  particularly in the area of the face and around body orifices. Skin hemorrhages and subserosal petechiae and ecchymoses may be observed in the stomach and intestines.  Subepicardial and subendocardial hemorrhages may also occur.
+
*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.
  
−
Adult rabbits of the genus Sylvilagus usually develop localized skin tumours resembling fibromas. Hares or young Sylvilagus rabbits may develop fibromatous to myxomatous nodules, however, lesions are usually mild and localized.
+
=====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.
  
−
==Prevention==
+
=====Histopathology=====
−
Vaccination and control of insect parasites are the most important means of disease prevention in domestic rabbits. In order to control fleas, wild rabbits should be kept away from pet rabbits and spot-on products may be used. Mosquito control can be achieved using insect repellent strips and fine mesh netting. The use of Vapona® strips and Nuvan Top® to prevent fly strike and myxomatosis is recommended (Lawton 1993).  Rearguard® (Novartis) has a licensed place in the prevention of fly-strike. Permethrin sprayed on mosquito netting to cover hutches has been recommended.
+
*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 - Anatomy & Physiology|spleen]].  Focal hemorrhage may be present in skin, kidneys, [[Lymph Nodes - Anatomy & Physiology|lymph nodes]], testes, heart, stomach, and intestinal walls. Myxoma cells may be present in [[Lymph Nodes - Anatomy & Physiology|lymph nodes]], [[Bone Marrow - Anatomy & Physiology|bone marrow]], uterus, ovaries, testes, and lungs.
  
−
The myxomatosis vaccine currently used in the UK is a live vaccine containing ''Shope fibroma'' virus (Nobivac Myxo, Intervet) - Shope's fibroma virus causes fibromatosis, a benign disease of Sylvilagus loridanus, an American lagomorph species. Antibodies made against ''Shope fibroma'' provide cross immunity against myxomatosis for three months. Intradermal vaccination is performed in order to achieve adequate immunity and annual booster vaccination is recommended; the manufacturers advise revaccination every six months in the event of "high risk"  exposure. Live attenuated vaccines have been used elsewhere in Europe but have been associated with other side effects such as immunosuppression.
+
====Epidemiology====
−
   
+
*Highly contagious and transmitted by direct or indirect contact with ocular or skin discharges or by mechanical vectors
−
===Note on “Shopes Viruses”===
+
*'''Mosquitoes''' act as mechanical vectors
−
Shope fibromavirus and Shope Papillomavirus (two distinct viruses) have dermal manifestations but are rare in the UK. Note the vaccine, Nobivac Myxo®; Intervet, contains the Shope Fibroma virus and is used to confer immunity against myxomatosis in rabbits in the UK.
+
*High ambient environmental temperatures are associated with increased survival of infected animals
−
*Shope papillomatosis is manifested mostly on the eyelids and ears as a pedunculated cornified surface over a fleshy central area. Spontaneous outbreaks have been recorded in domestic rabbits. Pedunculated cornified surface overlying a fleshy central area. After manual removal of the lesions, can extend to squamous cell carcinoma. Probably vector-spread (Meredith 2006). Papillomata on eyelids and ears. (Percy and Barthold 1993)
 
−
*Shope fibromavirus, the cause of Rabbit (Shope) Fibromatosis, leads to  flattened, firm, subcutaneous, freely movable tumours (=/<7cm diameter) on legs and feet sometimes on the muzzle and periorbital and perineal areas, and may persist for  several months. In young rabbits metastasis to abdominal bone marrow and abdominal viscera may occur. (Percy and Barthold 1993)
 
  
−
==Treatment==
+
====Differentials====
−
Although the mortality rate in affected rabbits is high, recovery is possible and treatment can be worthwhile:
+
*Shope fibroma virus
−
*Increase ambient temperature to 29.5°C - the virus is more virulent at lower ambient temps
+
**Localised benign tumours that spontaneously regress in adult immunocompetent rabbits
−
*Antibiotics that combat pasteurellosis, procaine penicillin (SC q 3-4d) or oxytetyracycline (SC q72h)
+
*Malignant rabbit fibroma virus
−
*“Good nursing“
+
**MRV is a recombinant between Myxoma virus and Shope fibroma virus.
−
*pro-kinetics if you can get them
+
**Causes a lethal disease with numerous primary and secondary tumours and immunosuppression.
−
*NSAID's
 
  
−
There are anecdotal reports of the use of Interferon in myxomatosis  - some cases recovered and some didn't. Did the ones that recovered receive the dose prior to clinical signs? How would you know that the rabbits were going to get the disease? Were they going to recover anyway, in spite of treatment? Rabbits that had full-blown clinical signs didn't recover, even when given Interferon. There were, apparently, no bad side-effects as a result of administration of interferon and clients might appreciate that the clinician was doing his best to help sick or in-contact rabbits. 
+
====Control====
 +
*Attenuated vaccines are used for farmed and pet rabbits
 +
*Wild suspect animals should be culled
  
−
Myxomatosis is spread rather erratically by contagion, more by vectors, so the use of “preventative treatments”  (interferon or vaccination) in the face of an outbreak is difficult to justify.
 
  
−
In-contact rabbits might not be actually incubating the disease as they might not be infected yet and therefore the vaccine has a better chance of working. If they are already incubating the disease the vaccine won’t work so there is definitely no benefit if clinical signs are established and no point using it as a therapy.
 
  
−
{{Learning
+
===Myxoma virus===
−
|literature search = [http://www.cabdirect.org/search.html?q=%28%28title%3A%28%22myxoma+virus%22%29%29%29+OR+%28%28title%3A%28%22myxomatosis%22%29%29%29&fq=sc%3A%22ve%22 Myxomatosis publications]
+
*Causes Myxomatosis in rabbits
−
}}
+
*Infectious myxomatosis is highly contagious and transmitted by direct or indirect contact with ocular or skin discharges or by mechanical vectors. 
 +
*Arthropod vectors such as mosquitoes and fleas provide the principal means of transmission.
 +
*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.
 +
*The naturally attenuated viruses cause a milder disease of longer duration which favors vector transmission and persistence of the virus in nature. 
 +
*High ambient environmental temperatures are associated with increased survival of infected animals.  Some authors consider the California strains of the virus (California rabbit fibroma virus) as distinct from the myxoma virus, while others feel that the antigenic differences do not justify the separate distinction.
  
−
==References==
+
====Pathogenesis====
−
*Fraser, S. G. (2009) '''Rabbit Medicine and Surgery for Veterinary Nurses''' ''Wiley-Blackwell''
+
*MYX infects several cell types including mucosal cells, lymphocytes, and fibroblasts.  
−
*Harcourt-Brown, F. (2002) '''Textbook of Rabbit Medicine''' ''Elsevier Health Sciences''
+
*In addition to primary and secondary tumor development, there is severe immunosuppression leading to overwhelming infections by opportunistic gram-negative bacteria. 
−
*Kayne, S. B., Jepson, M. H. (2004) '''Veterinary Pharmacy''' ''Pharmaceutical Press''
+
*Viral antigen is present within primary as well as secondary tumors.
−
*Ganiere, J.P. et al (1990) Etude clinique et experimentale de la myxomatose du lapin angora:  Le Point Vétérinaire  22 (129), 187 to 191
+
*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.
−
*Guaguere, E. (1995) Dermatoses of Pet Rodents and Rabbits. Procs 2nd European Congress of the Federation of European Companion Animal Veterinary Associations, Brussels, Belgium, 27-29 October 1995.  Pages 203-207
+
*With immunosuppression, severe secondary gram-negative bacterial infections of the conjunctiva and nasal passages occur.
−
*Harkness, J.E. (????) Rabbit husbandry and medicine in The Veterinary Clinics of North America - Small Animal Practice 17 (5) September 1987 Exotic Pet Medicine Pages 1019 -1044  W B Saunders Co Philadelphia ISSN 0195-5616
+
*Death follows within 14 days of inoculation.
−
*Lawton 1993
+
*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)
−
*Meredith, A. (2006) Dermatoses in BSAVA Manual of Rabbit Medicine and Surgery eds Meredith A and Flecknell P, 2nd Edition 2006, published by BSAVA Quedgley Glocs
+
**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.
−
*Okerman, L. (1994) Diseases of Domestic Rabbits. Blackwell Scien¬tific Publications 2nd Edition
+
*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.
−
*Percy, D. H. and Barthold, S. W. (1993) Pathology of Laboratory Rodents and Rabbits. Iowa sate University Press, Ames
+
*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.
  
−
{{review}}
+
====Pathology====
−
{{OpenPages}}
+
*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. 
−
[[Category:Leporipoxviruses]][[Category:Rabbit Viruses]]
+
*Skin hemorrhages and subserosal petechiae and ecchymoses may be observed in the stomach and intestines.  Subepicardial and subendocardial hemorrhages may also occur.
−
[[Category:Rabbit Dermatology]]
+
*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 - Anatomy & Physiology|lymph nodes]] and [[Spleen - Anatomy & Physiology|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 - Anatomy & Physiology|lymph nodes]], [[Bone Marrow - Anatomy & Physiology|bone marrow]], uterus, ovaries, testes, and lungs.
 +
 
 +
 
 +
 
 +
 
 +
[[Category:Leporipoxviruses]][[Category:Rabbit]]
 +
[[Category:To_Do_-_Viruses]]

Revision as of 22:51, 26 June 2010


 This article is still under construction.


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


Myxoma virus

  • Causes Myxomatosis in rabbits
  • Infectious myxomatosis is highly contagious and transmitted by direct or indirect contact with ocular or skin discharges or by mechanical vectors.
  • Arthropod vectors such as mosquitoes and fleas provide the principal means of transmission.
  • 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.
  • The naturally attenuated viruses cause a milder disease of longer duration which favors vector transmission and persistence of the virus in nature.
  • High ambient environmental temperatures are associated with increased survival of infected animals. Some authors consider the California strains of the virus (California rabbit fibroma virus) as distinct from the myxoma virus, while others feel that the antigenic differences do not justify the separate distinction.

Pathogenesis

  • MYX 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.
  • Viral antigen is present within primary as well as secondary tumors.
  • 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.
  • With immunosuppression, severe secondary gram-negative bacterial infections of the conjunctiva and nasal passages occur.
  • Death follows within 14 days of inoculation.
  • 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)
    • 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 and 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.
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