The effect of stress on the neuropathogenesis of Theiler's virus-induced demyelination as an animal model of multiple sclerosis

Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). To investigate the effects of stress on the pathogenesis of MS, we employed restraint stress (RST) in the Theiler??????s virus-induced demyelination (TVID) model, an animal model for human MS. Intracerebral inoculation of susceptible strain of mice with Theiler??????s murine encephalomyelitis virus (TMEV) results in a biphasic disease ?????? an acute encephalomyelitis and chronic demyelination. The establishment of persistent viral infection is critical in inducing immune-mediated demyelination during the chronic disease. The exposure of mice to RST prior to viral infection produced a stress response as evidenced by elevated circulating corticosterone (CORT). To further study the effect of stress on the immune response to TMEV infection and demyelination, we first examined the cytokine and chemokine response during the acute TMEV infection. We demonstrated that RST down-regulated the virus-induced expression of chemokines, Ltn, IP-10, RANTES, and pro-inflammatory cytokines, TNF, IFN and LT in both the brain and spleen during early infection. Histologically, a decreased pattern of inflammation was observed in the brain of restrained mice as compared to non-restrained mice. The increased viral titer was noted in the CNS of restrained mice and was correlated with the decreased production of pro-inflammatory cytokine, suggesting an impaired immune response by RST. Secondly, the duration of stress on the late demyelination was investigated. Repeated and chronically stressed SJL/J mice developed an early onset of clinical signs and a delayed onset was observed in acutely stressed mice. Both acute and chronic RST suppressed the antibody response to TMEV and stressed displayed a higher incidence of demyelination than non-restrained mice. Axonal loss was also noted in chronic stressed mice. Additionally, RST caused an increased systemic viral infection in extraneural organs during the acute infection and cardiotropic TMEV was isolated from the heart of stressed mice. Taken together, stress resulted in profound immunsuppression during acute infection, which may consequently increase the incidence of demyelination. The present study may be generalized in human MS which is potentially triggered by viral infection.