THE PATHOGENESIS OF CANINE DISTEMPER VIRUS INDUCED DEMYELINATION

Canine distemper (CD) was decribed for the first time in Europe in 1761 (Mitscherlich, 1938) and the virus etiology was confirmed by Carr6 in 1905 (Fankhauser, 1982). The natural host spectrum of CDV comprises all families of the order Carnivora (Deem et al., 2000). In humans, the participation of CDV in the pathogenesis of Paget's disease of bone (Gordon et al., 1991, Mee et al., 1998, Mee et al., 1999, Helfrich et al., 2000, Ooi et al., 2000) and multiple sclerosis (MS; Cook et al., 1978 and 1987, Vollmer and Waxman, 1991, Hodge and Wolfso, 1997, Hernan et al., 2001) has been speculated but lacks final verification. Canine distemper virus belongs to the genus morbillivirus of the Paramyxoviridae family and is closely related to measles virus (Pringle, 1999). CDV is an enveloped negative stranded virus (Kingsbury, 1990). It contains 6 structural proteins, the nucleocapsid (NP), phospho (P), and the large (L) protein (core proteins) and the membrane (M), hemagglutinin (H), and fusion (F) protein (surface proteins; Hall, 1980, Orvell, 1980, Diallo, 1990). The NP proteins catalyze transcription and replication in the host cell (Kingsbury, 1990). The M protein is involved in virus maturation as it connects the surface glycoproteins with the nucleocapsid (Kingsbury, 1990). The F protein manages the fusion of the virus with the host cell or the infected cell to the neighbour cell (Diallo, 1990). The H protein mediates the attachment of the virus to the host cell by neuraminic acid binding receptors (Hall et al., 1980; Kingsbury, 1990) and determines viral tropism and cytopathogenicity (von Messling et al., 2001). The function of the nonstructural proteins V and C is not clear. Recently, another non-structural protein has been detected that seems to allow virus replication in different species (Wang et al., 1998). CD9, a tetraspan transmembrane protein is associated with CDV induced cell-cell fusion but not virus-cell fusion (Schmid et al., 2000). Signalling lymphocyte activation molecules (SLAMs; CD150) act as cellular receptors for CDV and other morbilliviruses (Tatsuo et al., 2001, Tatsuo and Yanagi, 2002). There is only one serotype but there are several cocirculating genotypes of the virus (Haas et al., 1997). CDV strains display different properties. Some strains are associated with polioencephalitis (Snyder Hill) while others induce demyelinating leukoencephalitis (R252, A75-17; Summers and Appel, 1994).
Chapter D2 THE PATHOGENESIS OF CANINE DISTEMPER VIRUS INDUCED DEMYELINATION
A biphasic process
Wolfgang Baumg~irtner1 and Susanne Alldinger2 llnstitut fiir Pathologie der Tierdrztlichen Hochschule Hannover, Germany, 21nstitut fiir Veteriniir-Pathologie der Justus-Liebig-Universitiit Giessen, Geesis of Canine Distemper Virus induced demyelination
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Forms of canine distemper encephalitis
Canine distemper encephalitis can be classified in different subtypes according to morphological changes and brain areas affected. The type of neuropathological changes depend on the virus strain, age and immune status of the affected animal (Krakowka and Koestner, 1976, Summers et al., 1984a, Pearce-Kelling et al., 1990, Raw et al., 1992). Polioencephalitis is a rare manifestation of CDV infection and is predominantly observed in the cortex and the nuclei of the brain stem, neurons and protoplasmic astrocytes being the mainly affected cell populations (Baumg~irtner et al., 1999). Distemper polioencephalitis includes the subgroups "old dog encephalitis" (Lincoln et al., 1973, Imagawa et al., 1980), inclusion body encephalitis (Nesseler et al., 1997, and 1999), and post-vaccinal encephalitis (Hartley, 1974, Bestetti et al., 1978). In contrast, distemper ieukoencephalitis(DL) is a common finding and has been known for a long time. "Swelling of myelinated nerve fibres" was described by Cerletti in his work "about various forms of encephalitis and myelitis in dogs with canine distemper" as early as 1912. Scherer (1944), a German neuropathologist was among the first to compare DL white matter lesions to acute multiple sclerosis and he is the one who gave the impulse to use canine distemper as a model to study the pathogenesis of human demyelinating diseases (Koestner, 1975, DalCanto and Rabinowitz, 1982). Lesions in DL are mainly found in the cerebellum and less frequently in the cerebral white matter and the spinal cord (Baumg~irtner et al., 1999). Demyelination is consistently observed in fibre tracts in close proximity to the ventricles like the rostral medullary velum, cerebellar peduncles, and optic tracts (Summers and Appel, 1994). Studies tracking the route of CDV invasion and the mode of distribution of the virus in the brain showed ependymal infection and spread of the virus to the subependymal white matter indicating CNS infection along the cerebrospinal fluid (CSF) pathways (Vandevelde et al., 1985a). This finding matches the observation of Higgins et al. (1982a) who found a productive infection of the choroid plexus of the fourth ventricle and ependymal cells. In addition, hematogenous spread of CDV in the CNS is mediated by the association of the virus with lymphocytes (Rochborn, 1958, Summers et al., 1979) and plasma (Krakowka et al., 1989) or via infection of endothelial cells and subsequent spread to pericytes and astrocytic processes (Axtehelm, Baumg~irtner, 1989). DL lesions are categorized in acute, subacute noninflammatory, subacute inflammatory, chronic, and sclerotic (Krakowka et al., 1985, Alldinger et al., 1993, Gaedke et al., 1999). Acute lesions are characterized by focal vacuolation and mild astro- and microgliosis.