Abstract
Canine distemper virus (CDV)-induced demyelinating leukoencephalitis in dogs (Canis familiaris) is suggested to represent a naturally occurring translational model for subacute sclerosing panencephalitis and multiple sclerosis in humans. The aim of this study was a hypothesis-free microarray analysis of the transcriptional changes within cerebellar specimens of five cases of acute, six cases of subacute demyelinating, and three cases of chronic demyelinating and inflammatory CDV leukoencephalitis as compared to twelve non-infected control dogs. Frozen cerebellar specimens were used for analysis of histopathological changes including demyelination, transcriptional changes employing microarrays, and presence of CDV nucleoprotein RNA and protein using microarrays, RT-qPCR and immunohistochemistry. Microarray analysis revealed 780 differentially expressed probe sets. The dominating change was an up-regulation of genes related to the innate and the humoral immune response, and less distinct the cytotoxic T-cell-mediated immune response in all subtypes of CDV leukoencephalitis as compared to controls. Multiple myelin genes including myelin basic protein and proteolipid protein displayed a selective down-regulation in subacute CDV leukoencephalitis, suggestive of an oligodendrocyte dystrophy. In contrast, a marked up-regulation of multiple immunoglobulin-like expressed sequence tags and the delta polypeptide of the CD3 antigen was observed in chronic CDV leukoencephalitis, in agreement with the hypothesis of an immune-mediated demyelination in the late inflammatory phase of the disease. Analysis of pathways intimately linked to demyelination as determined by morphometry employing correlation-based Gene Set Enrichment Analysis highlighted the pathomechanistic importance of up-regulated genes comprised by the gene ontology terms “viral replication” and “humoral immune response” as well as down-regulated genes functionally related to “metabolite and energy generation”.
Highlights
Canine distemper virus (CDV) is a morbillivirus of the family Paramyxoviridae and the etiologic agent of distemper in dogs (Canis familiaris)
The transcriptional changes within all CDV leukoencephalitis subtypes were dominated by up-regulated genes related to the gene ontology terms ‘‘immunoglobulin-mediated immune response’’ and ‘‘complement activation, classical pathway’’
Hierarchical cluster analysis revealed a cluster of Differentially expressed probe sets (DEPs) highly up-regulated in chronic CDV leukoencephalitis only
Summary
Canine distemper virus (CDV) is a morbillivirus of the family Paramyxoviridae and the etiologic agent of distemper in dogs (Canis familiaris). Depending on the virulence of the respective CDV strain, the host’s age and immune status, dogs may either initiate a robust humoral immune response and recover or may develop a second viremic spread to multiple organs and tissues [4,5,6]. These dogs show various pathologic alterations including thymic atrophy, conjunctivitis, rhinitis, interstitial pneumonia, encephalitis, gastroenteritis, pustular dermatitis and hyperkeratosis of the foot pads and nose [3,7,8,9]. Some dogs may develop a chronically persistent or late-onset encephalitis [10,11]
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