Biphasic and regionally-restricted chemokine expression in the central nervous system in the Theiler's virus model of multiple sclerosis

Intracerebral infection of susceptible strains of mice with Theiler's murin e encephalomyelitis virus (TMEV) induces a biphasic disease characterized b y acute polioencephalitis followed by chronic demyelination and viral persi stence in the spinal cord white matter. There has been limited study of sol uble mediators responsible for the initial recruitment of inflammatory cell s into the gray matter, and the secondary influx into the white matter duri ng infection with TMEV. We used sensitive and specific RT-PCR/dot blot hybr idization assays to quantitate the relative levels of chemokine mRNA in the brains and spinal cords during the acute and chronic phases of TMEV infect ion in mice susceptible (E10.M, H-2(f)) and resistant (B10, H-2(b)) to viru s-induced demyelination. TMEV infection resulted in robust expression of mR NA for IP-10, RANTES, and MCP-l,but not GRO-alpha, in brains and spinal cor ds in both strains of mice within 5 days. By day 21, virus was cleared, inf lammation reduced, and expression of all three chemokines subsided to basel ine levels in the brains and spinal cords of resistant mice, and the brains of susceptible mice. Chemokine expression was also reduced in the spinal c ords of susceptible mice, corresponding to a shift in TMEV replication from the gray to the white matter. During the chronic, demyelinating phase of i nfection, there was a resurgence in IP-10, RANTES, and MCP-1 mRNA in spinal cords of susceptible B10.M mice, This study demonstrates the coordinated r egulation and regionally restricted expression of chemokines in a biphasic disease of the central nervous system and provides greater understanding of the mechanism by which inflammation is established and maintained in the C NS.