title: Viral mouse models of multiple sclerosis and epilepsy: Marked differences in neuropathogenesis following infection with two naturally occurring variants of Theiler's virus BeAn strain.
abstract: Following intracerebral inoculation, the BeAn 8386 strain of Theiler's virus causes persistent infection and inflammatory demyelinating encephalomyelitis in the spinal cord of T-cell defective SJL/J mice, which is widely used as a model of multiple sclerosis. In contrast, C57BL/6 (B6) mice clear the virus and develop inflammation and lesions in the hippocampus, associated with acute and chronic seizures, representing a novel model of viral encephalitis-induced epilepsy. Here we characterize the geno- and phenotype of two naturally occurring variants of BeAn (BeAn-1 and BeAn-2) that can be used to further understand the viral and host factors involved in the neuropathogenesis in B6 and SJL/J mice. Next generation sequencing disclosed 15 single nucleotide differences between BeAn-1 and BeAn-2, of which 4 are coding changes and 3 are in the 5'-UTR (5'-untranslated region). The relatively minor variations in the nucleotide sequence of the two BeAn substrains led to marked differences in neurovirulence. In SJL/J mice, inflammatory demyelination in the spinal cord and its clinical consequences were significantly more marked following infection with BeAn-1 than with BeAn-2. Both BeAn substrains caused lymphocyte infiltration and increase of MAC3-positive cells in the hippocampus, but hippocampal damage and seizures were only observed in B6 mice. Seizures occurred in one third of BeAn-2 infected B6 mice, but not in BeAn-1 infected B6 mice. By comparing individual mice by receiver operating characteristic (ROC) curve analysis, the severity of hippocampal neurodegeneration and amount of MAC3-positive microglia/macrophages discriminated seizing from non-seizing B6 mice, whereas T-lymphocyte brain infiltration was not found to be a crucial factor. These data add novel evidence to the view that differential outcome of infection may be not invariably linked to a distinct viral burden but to a finely tuned balance between antiviral immune responses that although essential for host resistance can also contribute to immunopathology.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bröer
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Hage
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Käufer
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Gerhauser
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Muneeb
authors.initials: M
authors.lastname: Anjum
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany; Department of Pathology, University of Veterinary Medicine Hannover, Germany.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Center for Systems Neuroscience, Hannover, Germany; Department of Pathology, University of Veterinary Medicine Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Center for Systems Neuroscience, Hannover, Germany; Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany. Electronic address: wolfgang.loescher@tiho-hannover.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000276:immunology / Q000473:pathology* / Q000821:virology; D004673:Encephalomyelitis, Acute Disseminated / Q000276:immunology / Q000473:pathology* / Q000821:virology; D004827:Epilepsy / Q000276:immunology / Q000473:pathology* / Q000821:virology; D005260:Female; D054884:Host-Pathogen Interactions; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology* / Q000821:virology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000378:metabolism; D013045:Species Specificity; D017945:Theilovirus / Q000235:genetics / Q000472:pathogenicity; D014774:Virulence
chemical_list: D012367:RNA, Viral
keywords: 5′ untranslated region (5′-UTR); Hippocampus; Multiple sclerosis; RNA sequencing; Seizures; Spinal cord