Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, South Africa
Canine distemper has affected dogs worldwide for centuries with descriptions of disease outbreaks in the European literature dating back to the 17th century. It was first formally described in dogs in 1905. Despite the introduction of modified live vaccines in the 1950s and their extensive uptake, the disease remains prevalent. With a mortality rate of around 50%, it is second only to rabies when it comes to virus-induced fatality in dogs. The disease has become a threat to many mammalians and threatens wildlife populations including large felids, seals, and dolphins. Indeed, one author has suggested that the disease name should be changed from canine distemper virus to carnivore distemper virus. In addition to being such a devastating disease across a wide host range, it has also emerged as a spontaneously occurring viral model to study the pathogenesis of demyelination in subacute sclerosing panencephalitis and multiple sclerosis of humans.
The virus is an enveloped, non-segmented negative-stranded RNA morbillivirus in the family Paramyxoviridae that is transmitted by close contact (usually via oronasal aerosol). It is shed in high titers from all body secretions during the acute phase of infection. The very young (typically less than 10 weeks of age) are usually protected by maternally derived antibody. Once this has waned, puppies are fully susceptible. The pathogenicity of the virus is variable and determined by virus strain, host immunity and age, and environmental factors. After initial exposure, dogs may mount a robust immune response and recover. It is estimated that as many as 75% of infections may actually be subclinical. Failing this, viraemia allows spread to lymphoid organs resulting in severe immunosuppression. Initial clinical signs include fever, lethargy, dehydration, anorexia, purulent oculonasal discharge, pneumonia, and diarrhoea (the so-called catarrhal phase of the disease). Some dogs will recover from this phase of the disease or they may progress to the usually irreversible neurological form. Neurological disease may however occur early in the disease course (concurrent with the catarrhal phase) or without any apparent previous illness. Virus may persist in some tissues, such as the CNS and nasal and foot pad skin, resulting in hyperkeratosis. Enamel hypoplasia occurs when the ameloblasts are damaged. The neurological signs are typically multifocal and occur from around 20 days after infection. They include circling, head tilt, nystagmus, partial or complete paralysis, seizures, myoclonus, and dementia.1
The virus is lymphotropic and very immunosuppressive causing long-lasting inhibition of both cellular and humoral immune responses rendering animals very susceptible to secondary infections. Following initial infection, lymphoid organs (spleen, lymph nodes, MALT, thymus) undergo collapse with dramatic depopulation. The CD4+ T cell population is more dramatically affected than the CD8+ population. Initial high viral loads are associated with very reduced cytokine responses. Lymphocyte loss occurs through direct viral damage and by apoptosis of uninfected lymphocytes. This depopulation is followed by a slow recovery and repopulation of lymphoid tissues. Despite this and the clearance of virus from the lymphoid organs, a functional recovery of these tissues does not occur and these animals remain in a state of immunosuppression with very blunted mitogenic responses. There is evidence to suggest that dendritic cells remain infected in the chronic disease phase and this may be a reason for the persisting immunosuppression. Additionally, there may be a role for a myeloid-derived suppressor cell population. Canine distemper virus (CDV) infection in ferrets (which are highly susceptible to infection) has proven to be a valuable tool for the study of the immunosuppressive action of the virus. Ferrets that survive the infection show an early Th1 response followed by a later Th2 response. A failure to show these sequential responses is associated with death.2
Invasion of the CNS is haematogenous with the virus being specifically leukocyte borne. The virus then tracks cerebrospinal fluid (CSF) invading ependymal and subependymal white matter. Penetration may also occur via the meninges. Infection of the CNS may occur as early as 5 days postinfection. Viral persistence appears to be an important mechanism of the demyelinating leukoencephalitis that is so typical of the more advanced neuropathology. Mechanisms of viral persistence in this phase of the disease appear to revolve around viral strategies to remain undetected by the immune system. The dominant lesions are restricted to the white matter and the region most affected is the cerebellum (especially the choroid plexus and periventricular regions). Astrocytes are the most important and dominant cell infected. In the early non-inflammatory areas of demyelination, over 60% of astrocytes within the lesion are infected and they represent over 90% of all infected cells. Histologically, the lesions consist of neuronal necrosis and neuronophagia with many infiltrating microglia, macrophages and T lymphocytes. Perivascular cuffing develops. The lesions are classified as acute, subacute non- inflammatory, subacute inflammatory, chronic and sclerotic lesions. Several phases of this pathology may occur concurrently within the same brain. The demyelination is now well described as a biphasic event. The initiation phase is a direct viral cytopathic process. The inflammatory plaque phase is an immune-mediated process. Early lesions show an influx of CD8+ T cells indicating an antibody-independent cytopathic mechanism. MHC II upregulates on the surface of several cell phenotypes as the local viral load decreases. This may indicate an increased role for the presentation of non-viral antigens in an autoimmune inflammatory and demyelinating process. The demyelination may even be regarded as collateral damage or as an 'innocent bystander' effect. Microglia are implicated in the release of proteolytic enzymes, phagocytosis, and the genesis of free oxygen radicals. Autoreactive T cells may be responsible for the observed induction of myelin-specific cellular immunity via epitope spreading secondary to myelin damage. In the later phases of the CNS disease, CD4+ T cells and B cells infiltrate the brain and there is a strong intrathecal antibody response. Cytokines from across the Th1-Th2 spectrum have been demonstrated in the blood of dogs with CNS CDV disease, which probably indicates a complex, stage-specific orchestrated or dysregulated cytokine milieu. An RT-PCR study demonstrated a skewed Th1 biased response with poor immunoregulatory cytokine (TGFβ and IL-10) expression which probably contributes to the progression of disease. In a recent fascinating study that evaluated gene expression in the cerebellum of CDV-infected dogs in various phases of demyelinating leukoencephalitis, the demyelination was confirmed to be a biphasic process. In subacute disease, multiple myelin genes displayed selective downregulation suggestive of an oligodendrocyte dystrophy. More chronic disease gene expression profiles were supportive of an immune-mediated demyelination.3
Canine distemper virus is here to stay for the foreseeable future. There are several avenues of investigation that should receive priority attention. I would suggest some of these would be: the ecology of the disease and the biology of the interface between domestic dogs and wildlife species that are at serious risk of infection; safe means of protecting wildlife species that are at risk; investigations into methods of vaccinating large numbers of feral dogs that live at the wildlife-domestic dog interface; and finally, there is much to be learnt from this dog disease as it provides a natural model of CNS inflammation and demyelination.
1. Martella V, Elia G, Buonavoglia C. Canine distemper virus. The Veterinary Clinics of North America Small Animal Practice. 2008;38(4):787–797, vii–viii.
2. Beineke A, Puff C, Seehusen F, Baumgartner W. Pathogenesis and immunopathology of systemic and nervous canine distemper. Veterinary Immunology and Immunopathology. 2009;127(1–2):1–18.
3. Ulrich R, Puff C, Wewetzer K, Kalkuhl A, Deschl U, Baumgartner W. Transcriptional changes in canine distemper virus-induced demyelinating leukoencephalitis favor a biphasic mode of demyelination. PLoS One. 2014;9(4):e95917.