Canine Distemper Virus (CDV)

Devoted to Tuzik who survived CDV but forever lost his personality and health (European outbreaks of CDV in 90s).

Taxonomy

Taxonomic lineage

Mononegavirales - Paramyxoviridae - Paramyxovirinae - Morbillivirus - Canine distemper virus

Strains

Canine distemper virus strain a92-27/4
Canine distemper virus strain a92-6
Canine distemper virus strain convac vaccine
Canine distemper virus strain Onderstepoort

The Canine Distemper Virus belongs to genus Morbillivirus in the Paramyxoviridae family. Paramyxoviruses are a family of non-segmented RNA viruses that includes major human pathogens such as Measles virus (MV) (Morbillivirus) and Respiratory Syncytial Virus (RSV) (Pneumovirus). The Morbillivirus contains four important human and domestic animal pathogenic viruses: Measles Virus (MV), Canine Distemper Virus (CDV), Rinderpest Virus (RPV) and Peste des Petits Ruminant Virus (PPRV). Other viruses from this genus affect dolphins and whales (Cetacean morbillivirus) and seals (Phocine distemper virus).

Brief facts

• Disease

  Canine distemper virus (CDV) is a causative agent of Canine distemper (CD), a disease in dogs and other carnivores that has been known for centuries worldwide. This highly contagious systemic disease that is spread by aerosol of body secretions (especially, respiratory) and excretions, including urine, has the highest fatality rates after rabies. The virus was first isolated by Carré in 1905.

• Host range

  Many different species of the order Carnivora are susceptible to CD and the mortality rate varies greatly between species. Ailuridae (red panda family), Canidae (dog, coyote, wolf, fox), Hyaenidae (hyenas), Mustelidae (weasel, mink, badger, martens and others), Procyonidae (raccoon, coati and olingo), Ursidae (bears), Viverridae (civets) and more recently Felidae (cats) have been reported to be susceptible to CDV infection.
  Since 1988, an expansion of the already broad natural host spectrum of CDV has occurred. Spontaneous, clinically overt infections with CDV-like morbilliviruses has been described in captive Japanese macaques (Macaca fuscata), collared peccaries (Tayassu tajacu) and Lake Baikal seals (Phoca sibirica). Distemper outbreaks have been observed for the first time in lions, tigers and jaguars in several North Americans zoos and safari parks. In 1994, CDV killed up to 30% of the free-ranging lions and an unknown number of hyenas in the Tanzanian Serengeti National Park.

• Epidemiology

  Temporal fluctuations in disease prevalence have been observed, with increased frequency during cold season. Age-related susceptibility to infection (3-6 month-old pups are more susceptible than newborn adult dogs) correlates with the decline in maternally derived immunity, because young pups are protected by passive immunity and most adult dogs are protected by vaccination.

• Domestic cats

  Canine Distemper disease is different from Feline distemper or Feline panleukopenia. The former is caused by virus that belongs to a group of single-stranded negative-strand RNA viruses and causative agent of the latter belongs to single-stranded DNA viruses (genus Parvovirus).
  Domestic cats are known to be susceptible to experimental CDV infection, but evidence for natural infections, clinical disease or shedding of infectious virus has never been observed.

• Humans

  There are indications for possible involvement of CDV in Multiple Sclerosis in humans. CDV in its demyelinating form in dogs may be a naturally occurring model for MS in humans. The similarities between the demyelinating encephalitis seen in dogs infected with CDV and humans with MS are remarkable. Laboratory evidence of association between CDV and MS obtained in some studies includes higher titers of serum antibodies to CDV in MS patients compared with controls, and presence of morbillivirus antigens in brain tissues from MS patients.

• Vaccines

  Modified CDV-like vaccines became available in the 1950s and have been widely used since 1960s, leading to drastically reduced impact of distemper on dog populations. Current licensed CDV vaccines are based on strains that have been attenuated by serial passage, either on canine kidney cells (Rockborn strain), hem eggs (Onderstepoort strain) or chicken fibroblast cultures (Lederle strain). Rockborn strain-based vaccines were shown to induce a higher titer of virus-neutralizing antibodies compared to Onderstepoort derivatives. Although generally safe for use in healthy and immunocompetent dogs, both vaccines, especially Rockborn, remain virulent and potentially lethal for several wild carnivores such as red pandas, black-footed ferrets and African wild dogs.
  Results of vaccines Duration of immunity (DOI) studies show that the modified live CDV vaccines containing Rockborn or Snyder Hill strain have a minimum DOI of 7 years based on challenge and up to 15 years based on serology. The minimum DOI for the modified live CDV vaccines with the Onderstepoort strain is 5 years based on challenge and 9 years based on serology.
  To overcome the interference of maternally derived antibodies, pups should be vaccinated at 6 to 8 weeks of age and again after 2 to 4 weeks. Re-vaccination is recommended every 3 years or performed annually.
  Despite high vaccination rates, a resurgence of distemper among dog populations has been observed in the late 1980s, culminating in major outbreaks in France, Germany and Scandinavia during 1991-1995.

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Genome organization and structure

Morbilliviruses are enveloped pleiomorphic particles with sizes ranging from 300 to 600 nm. They are negative-stranded non-segmented RNA viruses. Their genome, a single-stranded RNA, about 16,000 nucleotides long, has to be transcribed by their own polymerase into at least six mRNAs. Each mRNA is translated into one protein, while a part of P mRNA which is read in two different frames leads to P and C proteins.

At each end of the genomic RNA, there is a short region called leader (56 nucleotides long at the 3' end, and 37 nt long at the 5' end) which is thought to contain the promoter for binding the polymerase to nucleocapsid template. Each gene starts with UCCC or UCCU preceded by the intergenic trinucleotide GAA (but GCA for H-L intergenic). The RNA polymerase enters into the genome from the 3' end and starts transcribing it into monocistronic messengers.

• Nucleoprotein Protein N. A major viral protein with molecular weight ~60 kDa. It protects the genome and is considered to be a major cross-reacting antigen.
• Polymerase-
  associated
  protein Protein P. A phosphorilated protein associated with N and L in the nucleocapsid that plays a role in RNA transcription and replication. Molecular weight deduced from nucleotide sequence is 54.6 kDa.
• Nonstructural
  protein Protein C. The CDV P gene, as in measles virus (MV), encodes two proteins: P and C. The function of C protein is unclear.
• Matrix protein Protein M. The matrix protein lies under the lipid bilayer and serves as a link between the nucleocapsid and the two surface glycoproteins (H and F). It is thought to play an important role during maturation of the virus.
• Fusion protein Protein F. One of the viral surface glycoproteins. It mediates fusion between the virus and the infected cell or between the infected cell and an adjacent cell, playing an essential role in spreading the infection within the host. Membrane fusion between the host cells leads to formation of syncytia.
• Hemagglutinin
  protein Protein H. The second viral membrane glycoprotein, serves to attach the virus to the host cell, which is the first step of infection. This proteins is most genetically variable among all CDV proteins (approx. 10% vs. 4%). Based on the pronounced genetic diversity in the H gene, it is possible to characterize most CDV field strains into six major genetic lineages, referred to as America-1 and -2, Asia-1 and -2, European and Arctic.
• Large protein Protein L. The minor viral protein. Its gene is the last transcribed by the virus. In association with N and P proteins and the genomic RNA it forms the nucleocapsid. The estimated molecular weight is about 200 kDa.

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Disease progression

• Acquisition The virus enters the new host by the nasal or oral route in aerosols. Respiratory tract macrophages and monocytes represent the first cell type to pick up and propagate the virus. Following this local burst of viral replication, the pathogen is then disseminated by lymphatics and blood to distant hematopoietic tissues during the first phase of the disease.
• Incubation period Lasts from 1 to 4 weeks or more. Transient fever reaches a peak 3 to 6 days after infection and is associated with the initial viral spread in the body and primary virus replication in the lymphoid tissues (spleen, thymus, lymph nodes, bone marrow, mucosa-associated lymphatic tissues (MALT), macrophages in the lamina propria of the gastrointestinal tract and hepatic Kupffer cells). Infection of these tissues is associated with severe long lasting immunosuppression. First clinical signs are characterized by lethargy, loss of appetite, slight depression, ocular and nasal discharge, and tonsillitis.
• Acute disease By days 6 to 9 after infection, virus spreads from lymphoid tissues to the epithelial cells in most organs. This stage of disease is characterized by high fever, and results in infection of tissues throughout the body. This stage is critical for the disease outcome. If the dog develops a strong immune response, the virus gets cleared from the tissues and the animal completely recovers. In dogs with weak immune response, the virus continues to replicate and spreads massively throughout the body including Central Nervous System (CNS) killing most animals by 2 to 4 weeks of infection.
  • Early clinical
    presentations As a result of the epithelial localization, respiratory, intestinal, and dermatologic signs develop within 10 days after infection often exacerbated by secondary bacterial infections. The symptoms include nasal discharge, coughing, pneumonia, diarrhea, vomiting, and dermal pustules. Enamel hypoplasia and hyperkeratosis of the foot pads and nose are typical signs of CDV. By 10^th of infection virus may reach CNS, long before the first lesions occur.
    
  • Neurologic
    presentations The initial demyelinating lesions occur around three weeks post infection after which neurologic signs such as circling, head tilt, involuntary eye movement (nystagmus), partial or complete paralysis, convulsions, and dementia may be observed. Involuntary jerky twitching or contraction of muscles and convulsions preceded by chewing movements of the mouth are considered typical of CDV infection.
    In acute infection, primary demyelination in brain takes place during severe immunosuppression, is not inflammatory and coincides with productive infection in microglia and astrocytes of the white matter. In contrast, infection of oligodendrocytes that are responsible for myelin synthesis is restricted to viral transcription. The restricted infection and other factors may account for their metabolic dysfunction leading to decreased myelin production and degeneration that lies at the base of the demyelinating process.
  • Chronic disease In some surviving dogs virus may continue to persist in CNS, and the disease evolves discontinuously but progressively. The mechanism of viral persistence is not yet understood but is most likely related to virus modifications that allow it to become less detectable by the immune system and to escape immune responses.
    Some dogs may still recover, but compulsive and uncoordinated movements like head pressing, pacing, and others tend to persist.
    In chronic forms of disease, the demyelination lesions are attributable to an inflammatory reaction caused by an CDV-specific immune response ("innocent bystander" mechanism) and by persistence of CDV in the tissues.
    A rare outcomes of CDV infection that do not occur in nature are chronic encephalomyelitis of mature dogs, termed old dog encephalitis (ODE) and polioencephalitis caused by Snyder Hill CDV strain used for vaccination.

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Treatment

Anti-CDV drugs are not available. Treatment consists of supportive care and antibiotics and is aimed at preventing and suppressing the secondary bacterial infections. The dehydration, brought about by diarrhea, is treated with intravenous electrolyte fluids. Injections of essential vitamins and nutrients help dogs who are unable to eat.

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References

• Vandevelde M, Zurbriggen A. Demyelination in canine distemper virus infection: a review. Acta Neuropathol. 2005 Jan;109(1):56-68.
• Harder TC, Osterhaus AD. Canine distemper virus--a morbillivirus in search of new hosts? Trends Microbiol. 1997 Mar;5(3):120-4.
• Schultz RD. Duration of immunity for canine and feline vaccines: a review. Vet Microbiol. 2006 Oct 5;117(1):75-9.
• Beineke A, Puff C, Seehusen F, Baumgärtner W. Pathogenesis and immunopathology of systemic and nervous canine distemper. Vet Immunol Immunopathol. 2009 Jan 15;127(1-2):1-18.
• Vandevelde M, Zurbriggen A. The neurobiology of canine distemper virus infection. Vet Microbiol. 1995 May;44(2-4):271-80.
• Diallo A. Morbillivirus group: genome organisation and proteins. Vet Microbiol. 1990 Jun;23(1-4):155-63.
• Lincoln JA, Hankiewicz K, Cook SD. Could Epstein-Barr virus or canine distemper virus cause multiple sclerosis? Neurol Clin. 2008 Aug;26(3):699-715, viii.
• Hughes RA, Russell WC, Froude JR, Jarrett RJ. Pet ownership, distemper antibodies and multiple sclerosis. J Neurol Sci. 1980 Sep;47(3):429-32.
• Appel MJ, Summers BA. Pathogenicity of morbilliviruses for terrestrial carnivores. Vet Microbiol. 1995 May;44(2-4):187-91.
• Martella V, Elia G, Buonavoglia C. Canine distemper virus. Vet Clin North Am Small Anim Pract. 2008 Jul;38(4):787-97, vii-viii.

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