A 40-cM Region on Chromosome 14 Plays a Critical Role in the Development of Virus Persistence, Demyelination, Brain Pathology and Neurologic Deficits in a Murine Viral Model of Multiple Sclerosis

Theiler virus persists and induces immune-mediated demyelination in susceptible mice and serves as a model of multiple sclerosis. Previously, we identified 4 markers-D14Mit54, D14Mit60, D14Mit61 and D14Mit90-in a 40-cM region of chromosome 14 that are associated with demyelination in a cross between susceptible DBA/2 and resistant B10.D2 mice. We generated congenic-inbred mice to examine the contribution of this 40-cM region to disease. DBA Chr.14^B10 mice, containing the chromosomal segment marked by the microsatellite polymorphisms, developed less spinal cord demyelination than did DBA/2 mice. More demyelination was found in the reciprocal congenic mouse B10.D2 Chr.14^D2 than in the B10.D2 strain. Introduction of the DBA/2 chromosomal region onto the B10.D2 genetic background resulted in more severe disease in the striatum and cortex relative to B10.D2 mice. The importance of the marked region of chromosome 14 is indicated by the decrease in neurological performance using the Rotarod test during chronic disease in B10.D2 Chr.14^D2 mice in comparison to B10.D2 mice. Viral replication was increased in B10.D2 Chr.14^D2 mice as determined by quantitative real-time RT-PCR. These results indicate that the 40-cM region on chromosome 14 of DBA/2 mice contributes to viral persistence, subsequent demyelination, and loss of neurological function.