RESUMO
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.
Assuntos
Astrócitos/virologia , Doenças Desmielinizantes/veterinária , Vírus da Cinomose Canina/patogenicidade , Cinomose/virologia , Encefalomielite Aguda Disseminada/veterinária , Proteína Glial Fibrilar Ácida/genética , Animais , Aquaporina 4/genética , Aquaporina 4/imunologia , Astrócitos/imunologia , Astrócitos/patologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/virologia , Coenzima A Ligases/genética , Coenzima A Ligases/imunologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Progressão da Doença , Cinomose/genética , Cinomose/imunologia , Cinomose/patologia , Vírus da Cinomose Canina/imunologia , Cães , Encefalomielite Aguda Disseminada/genética , Encefalomielite Aguda Disseminada/patologia , Encefalomielite Aguda Disseminada/virologia , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/imunologia , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/imunologia , Ácido Glutâmico/imunologia , Ácido Glutâmico/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Proteoglicanas/genética , Proteoglicanas/imunologia , Transdução de Sinais , Survivina/genética , Survivina/imunologia , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/imunologiaRESUMO
Canine distemper virus (CDV) infection causes immunosuppression and demyelinating leukoencephalitis in dogs. In viral diseases, an ambiguous function of regulatory T cells (Treg), with both beneficial effects by reducing immunopathology and detrimental effects by inhibiting antiviral immunity, has been described. However, the role of Treg in the pathogenesis of canine distemper remains unknown. In order to determine the effect of CDV upon immune homeostasis, the amount of Foxp3(+) Treg in spleen and brain of naturally infected dogs has been determined by immunohistochemistry. In addition, splenic cytokine expression has been quantified by reverse transcriptase polymerase chain reaction. Splenic depletion of Foxp3(+) Treg was associated with an increased mRNA-expression of tumor necrosis factor and decreased transcription of interleukin-2 in the acute disease phase, indicative of disturbed immunological counter regulation in peripheral lymphoid organs. In the brain, a lack of Foxp3(+) Treg in predemyelinating and early demyelinating lesions and significantly increased infiltrations of Foxp3(+) Treg in chronic demyelinating lesions were observed. In conclusion, disturbed peripheral and CNS immune regulation associated with a reduction of Treg represents a potential prerequisite for excessive neuroinflammation and early lesion development in canine distemper leukoencephalitis.
