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The role of sphingosine-1-phosphate in host defense and disease following infection with a neurotropic coronavirus

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Multiple sclerosis (MS) is a complex neurological disease that causes permanent disability in young adults. The cause of MS is still unknown, although both genetic and environmental factors are believed to play an important role in onset of disease. FTY720 is the first oral drug approved by the FDA to treat relapsing-remitting forms of MS presumably by inhibiting the egress of autoreactive T cells from the lymph nodes thereby preventing infiltration into the central nervous system (CNS). Treated-patients display a reduction in relapses, a decrease in new lesion formation and diminished brain volume loss shown by MRI.

We employ a viral model of demyelination to study various aspects related to the pathogenesis of MS. Intracerebral infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in an acute encephalomyelitis followed by chronic immune-mediated demyelination, that is similar both clinically and histologically to MS. The primary focus of research of this dissertation is to investigate whether FTY720 affects the host response and/or disease progression in response to JHMV infection of the CNS. Administration of FTY720 to JHMV-infected mice resulted in increased mortality associated impaired ability to control CNS viral replication that correlated with dampened accumulation of virus-specific CD4+ and CD8+ T cells. Treatment with FTY720 did not affect proliferation, cytokine secretion, or cytolytic activity by virus-specific T cells. Administration of FTY720 resulted in diminished severity of JHMV-induced demyelination associated with reduced T cell accumulation within the CNS. These findings indicate that FTY720 mutes effective antiviral immune responses by limiting infiltration of virus-specific T cells within the CNS following infection with a neurotropic virus.

Engraftment of mouse neural progenitor cells (NPCs) into the CNS of JHMV-infected mice with established demyelination results in extensive remyelination and axonal sparing. FTY720 readily penetrates the CNS. Therefore, the effect of FTY720 treatment on the biology of NPC's following CNS transplantation into JHMV-infected mice was examined. FTY720 increased NPC migration and proliferation within the spinal cord but did not diminish neuroinflammation, decrease the severity of demyelination nor increase remyelination. Therefore, FTY720 does not enhance the therapeutic potential of NPCs in a model of chronic-induced demyelination.

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