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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.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

Bröer S,Hage E,Käufer C,Gerhauser I,Anjum M,Li L,Baumgärtner W,Schulz TF,Löscher W

doi

10.1016/j.nbd.2016.12.020

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

121-132

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(16)30301-1

journal_volume

pub_type

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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.