RESUMO
Multiple sclerosis (MS) is a devastating CNS disease of unknown origin. Multiple factors including genetic background, infection, and psychological stress affect the onset or progression of MS. Theiler's murine encephalomyelitis virus (TMEV) infection is an animal model of MS in which aberrant immunity leads to viral persistence and subsequently results in demyelination that resembles MS. Here, we examined how stress during acute TMEV infection altered virus-specific cell mediated responses. Using immunodominant viral peptides specific for either CD4(+) or CD8(+) T cells, we found that stress reduced IFN-gamma producing virus-specific CD4(+) and CD8(+) T cells in the spleen and CD8(+) T cells CNS. Cytokine production by cells isolated from the CNS or spleens following stimulation with virus or viral peptides, indicated that stress decreased both type 1 and type 2 responses. Glucocorticoids were implicated in the decreased T cell function as the effects of stress were partially reversed by concurrent RU486 administration but mimicked by dexamethasone. As T cells mediate viral clearance in this model, our data support the hypothesis that stress-induced immunosuppression may provide a mechanism for enhanced viral persistence within the CNS.
Assuntos
Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/psicologia , Imunidade Celular/fisiologia , Estresse Psicológico/imunologia , Estresse Psicológico/psicologia , Theilovirus/imunologia , Doença Aguda , Animais , Western Blotting , Peso Corporal/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Fator de Transcrição GATA3/imunologia , Tolerância Imunológica/imunologia , Tolerância Imunológica/fisiologia , Camundongos , Restrição Física , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th1/metabolismo , Células Th2/imunologia , Theilovirus/isolamento & purificação , Ensaio de Placa ViralRESUMO
Previous research has shown that chronic restraint stress exacerbates Theiler's virus infection, a murine model for CNS inflammation and multiple sclerosis. The current set of experiments was designed to evaluate the potential role of glucocorticoids in the deleterious effects of restraint stress on acute CNS inflammatory disease. Exposure to chronic restraint stress resulted in elevated levels of corticosterone as well as increased clinical scores and weight loss (Experiment 1). In addition, corticosterone administration alone exacerbated behavioral signs of TMEV-induced sickness (i.e. decreased body weight, increased symptoms of encephalitis, and increased mortality) and reduced inflammation in the CNS (Experiment 2). Infected subjects receiving exogenous corticosterone showed exacerbation of acute phase measures of sickness and severe mortality as well as decreased viral clearance from CNS (Experiment 3). These findings indicate that corticosterone exposure alone is sufficient to exacerbate acute CNS inflammatory disease.
Assuntos
Infecções por Cardiovirus/etiologia , Infecções por Cardiovirus/fisiopatologia , Glucocorticoides/administração & dosagem , Theilovirus/patogenicidade , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Infecções por Cardiovirus/metabolismo , Infecções por Cardiovirus/mortalidade , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Glucocorticoides/metabolismo , Masculino , Meningite/etiologia , Meningite/patologia , Meningite/virologia , Camundongos , Camundongos Endogâmicos CBA , Mortalidade , Índice de Gravidade de Doença , Estresse Psicológico/fisiopatologia , Análise de SobrevidaRESUMO
Social stress alters the acute phase of Theiler's virus infection (TMEV), a model of multiple sclerosis. Stress applied prior to infection had deleterious disease outcomes, while stress applied concurrent with infection was protective. The current study examined multiple behavioral (motor impairment, open field activity) and immunological measures (IL-6, antibodies to virus and myelin proteins) in both the acute and chronic phases of TMEV. It was found that stress applied prior to infection exacerbated disease outcomes, while concurrent application was protective in both disease phases.