Although stress and neuroinflammatory processes are implicated in the pathogenesis of infectious and autoimmune diseases of the CNS, few studies have examined how stress and neuroinflammation interact to determine disease vulnerability. The proposed experiments investigate the role central proinflammatory cytokine expression in mediating the adverse behavioral and neuroinflammatory effects of repeated social disruption stress (SDR) on Theiler's murine encephalomyelitis (TMEV) infection, an animal model of CNS infection and multiple sclerosis. Repeated exposure to SDR exacerbates TMEV- induced sickness behaviors, motor impairment, CNS inflammation, and disrupts viral clearance from CNS. Preliminary data suggest a role for the central proinflammatory cytokine interleukin-6 (IL-6) in mediating the deleterious effects of SDR on sickness/motor behaviors and immunity during acute TMEV infection; however, the exact mechanisms remain unknown. The objective of this grant application is to determine whether the adverse behavioral and neuroimmune effects of SDR on acute and chronic TMEV infection are mediated by the sensitization of virus-induced cytokine expression. The proposed experiments test the hypothesis that SDR exacerbates TMEV infection through cross-sensitization of central cytokine expression.
Aim 1 will establish whether stress- induced increases in central IL-6 mediate the adverse effects of SDR on acute TMEV- infection through cross-sensitization of virus-induced cytokine expression. This will be accomplished by determining whether SDR increases virus-induced cytokine expression, sickness behaviors, motor impairment, and suppresses specific anti-viral immune responses during acute TMEV infection. Moreover, this aim will determine whether central administration of a neutralizing antibody to IL-6 prevents the adverse effects of SDR during early infection (necessity) and whether pretreatment with intracerebral IL-6 prior to TMEV infection mimics the adverse effects of SDR (sufficiency).
Aim 2 will determine whether stress-induced increases in central IL-6 mediate the adverse effects of SDR during the chronic autoimmune demyelinating phase of TMEV infection. This will be accomplished by examining whether SDR increases virus-induced cytokine expression, demyelination, DTH responses, and antibody responses to myelin and TMEV, and whether stress-induced increases in central IL-6 are necessary and sufficient to exacerbate chronic disease.
Relatively little is known about the effects of social on multiple sclerosis, and the mechanisms through which stress alters the expression of sickness behaviors and disease pathogenesis. The proposed studies could have broad implications for understanding the role of stress and cytokine expression in MS and other inflammatory neurodegenerative diseases. Understanding the mechanisms by which social stress exacerbates the severity of a virally initiated autoimmune disease could lead to the development of interventions aimed at preventing or reversing the adverse effects of social stress on vulnerability to MS other stress-related inflammatory diseases. ? ? ?
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