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.14B10 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.14D2 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.14D2 mice in comparison to B10.D2 mice. Viral replication was increased in B10.D2 Chr.14D2 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.
Nakane
Shunya
S
Department of Neurology, Mayo Clinic and Foundation, Rochester, Minn 55905, USA.
Zoecklein
Laurie J
LJ
Gamez
Jeffrey D
JD
Papke
Louisa M
LM
Pavelko
Kevin D
KD
Bureau
Jean-François
JF
Brahic
Michel
M
Pease
Larry R
LR
Rodriguez
Moses
M
D000818:Animals; D001522:Behavior, Animal; D001927:Brain Diseases / Q000662:veterinary / Q000821:virology*; D002875:Chromosomes; D003711:Demyelinating Diseases / Q000662:veterinary / Q000821:virology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008581:Meningitis / Q000473:pathology / Q000821:virology; D051379:Mice; D020297:Mice, Congenic; D008811:Mice, Inbred DBA; D018895:Microsatellite Repeats; D009043:Motor Activity / Q000502:physiology; D009103:Multiple Sclerosis / Q000235:genetics* / Q000662:veterinary / Q000821:virology; D011051:Poliomyelitis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods / Q000662:veterinary; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000821:virology; D017945:Theilovirus / Q000378:metabolism / Q000472:pathogenicity; D013997:Time Factors; D014771:Virion / Q000378:metabolism
D012333:RNA, Messenger