Abstract
Canine distemper virus (CDV) causes a fatal demyelinating leukoencephalitis in young dogs resembling human multiple sclerosis. Astrocytes are the main cellular target of CDV and undergo reactive changes already in pre-demyelinating brain lesions. Based on their broad range of beneficial and detrimental effects in the injured brain reactive astrogliosis is in need of intensive investigation. The aim of the study was to characterize astrocyte plasticity during the course of CDV-induced demyelinating leukoencephalitis by the aid of immunohistochemistry, immunofluorescence and gene expression analysis. Immunohistochemistry revealed the presence of reactive glial fibrillary acidic protein (GFAP)+ astrocytes with increased survivin and reduced aquaporin 4, and glutamine synthetase protein levels, indicating disturbed blood brain barrier function, glutamate homeostasis and astrocyte maladaptation, respectively. Gene expression analysis revealed 81 differentially expressed astrocyte-related genes with a dominance of genes associated with neurotoxic A1-polarized astrocytes. Accordingly, acyl-coA synthetase long-chain family member 5+/GFAP+, and serglycin+/GFAP+ cells, characteristic of A1-astrocytes, were found in demyelinating lesions by immunofluorescence. In addition, gene expression revealed a dysregulation of astrocytic function including disturbed glutamate homeostasis and altered immune function. Observed findings indicate an astrocyte polarization towards a neurotoxic phenotype likely contributing to lesion initiation and progression in canine distemper leukoencephalitis.
Highlights
Canine distemper is a fatal disease in dogs, caused by a single-stranded, negative-sense RNA virus of the genus Morbillivirus, which is closely related to the human measles virus
Astrocytes play a central role in maintaining normal central nervous system (CNS) physiology and critically control the response to brain injury and neurological diseases
Phenotypical and molecular analyses of the present study revealed an altered metabolism and neurotoxic properties of reactive astrocytes in Canine distemper virus (CDV) lesions, which have the potential to disturb neurotransmitter uptake and blood brain barrier homeostasis
Summary
Canine distemper is a fatal disease in dogs, caused by a single-stranded, negative-sense RNA virus of the genus Morbillivirus, which is closely related to the human measles virus. Astrocytes regulate water transport through aquaporins[16], synthesize metabolic substrates such as glycogen, sterols and lipoproteins[17,18] and support neighboring neurons through the export of glucose and lactate[19] They are able to respond to glutamatergic www.nature.com/scientificreports/. Www.nature.com/scientificreports neurotransmission by influencing the tone of arterioles and regulate the local blood supply[20] Another key function is the removal of neurotransmitters, such as glutamate, from the synaptic cleft by specific transporters and subsequent degradation by glutamine synthetase (glutamate glutamine cycle), preventing excitotoxic cell death of neurons and myelin producing oligodendrocytes[17,21]. Aims of this study were to (i) determine phenotypical changes of astrocytes in demyelinating lesions, (ii) to characterize astrocytic expression pattern by the aid of gene expression analyses in CDV-infected dogs and (iii) to investigate astrocyte polarization regarding the A1/A2-phenotype in canine distemper
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