Molecular characterization of a nondemyelinating variant of Daniel's strain of Theiler's virus isolated from a persistently infected glioma cell line (original) (raw)
Related papers
Journal of Virology, 2011
The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, with persistence of the virus in the central nervous system (CNS) for the life of the mouse. Although TMEV-induced demyelinating disease (TMEV-IDD) is thought to be immune mediated, there is also evidence that supports a role for the virus in directly inducing demyelination. In order to clarify the function of DA virus genes, we generated a transgenic mouse that had tamoxifen-inducible expression of the DA L-coding region in oligodendrocytes (and Schwann cells), a cell type in which the virus is known to persist. Tamoxifen-treated young transgenic mice usually developed an acute progressive fatal paralysis, with abnormalities of the oligodendrocytes and Schwann cells and demyelination, but without significant lymphocytic infiltration; later treatment led to transi...
A Subgenomic Segment of Theiler's Murine Encephalomyelitis Virus RNA Causes Demyelination
Journal of Virology, 2008
The DA strain of Theiler's murine encephalomyelitis virus (TMEV) causes a persistent central nervous system (CNS) infection of mice with a restricted virus gene expression and induces an inflammatory demyelinating disease that is thought to be immune mediated and a model of multiple sclerosis (MS). The relative contribution of virus vis-à-vis the immune system in the pathogenesis of DA-induced white matter disease remains unclear, as is also true in MS. To clarify the pathogenesis of DA-induced demyelination, we used Cre/ lox P technology to generate a transgenic mouse that has tamoxifen (Tm)-inducible expression of a subgenomic segment of DA RNA in oligodendrocytes and Schwann cells. Tm-treated young transgenic mice developed progressive weakness leading to death, with abnormalities of oligodendrocytes and Schwann cells and demyelination, but without inflammation, demonstrating that DA virus can play a direct pathogenic role in demyelination. Tm treatment of mice at a later ag...
Journal of General Virology, 1990
Theiler's murine encephalomyelitis virus (TMEV) induces demyelinating disease which is associated with persistent virus infection of the central nervous system. To study the interaction between TMEV and host cells, we infected the G26-20 glioma cell line in vitro, and this resulted in a lytic infection in which most, but not all, cells were killed. Surviving cells divided and formed a viable monolayer in which a small proportion of cells displayed viral cytopathic effects. Levels of virus produced by these cultures over a 6 month period fluctuated between 6 and 8 loglo p.f.u.lml as measured by viral plaque assay. Similarly, the percentage of cells producing both viral antigen and viral RNA, as measured by a simultaneous immunoperoxidase]in situ hybridization technique, varied between 5 and 30%. Although persistently infected cultures were susceptible to challenge by both vesicular stomatitis virus and herpes simplex virus, they were resistant to infection by homologous viruses. Interferon activity was not identified. TMEV isolated from passage 12 produced smaller plaques than wild-type Daniels strain virus (wt-DAV) on L-2 cell monolayers. In contrast to demyelination induced in SJL/J mice after intracerebral inoculation with wt-DAV, mice infected with the small plaque variant virus failed to develop viral persistence or chronic demyelination. However, following immunosuppression by total body irradiation, SJL/J mice infected with the small plaque variant developed viral persistence but no demyelination. Characterization of the biochemical and molecular determinants of the variant will lead to a better understanding of determinants important in viral persistence.
Journal of Virology, 2009
The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection associated with an inflammatory white matter demyelinating disease. TO subgroup strains synthesize an 18-kDa protein, L*, out of frame with the polyprotein from an initiation codon 13 nucleotides downstream from the polyprotein's AUG codon. We previously generated a mutant virus from our infectious DA full-length clone that has a change of the L* AUG codon to ACG (with no change in the polyprotein's amino acid sequence). Studies of this mutant virus showed that L* was key to the TO subgroup phenotype because the mutant had a decreased ability to persist and demyelinate. This work was initially called into question because a similar mutant derived from a different full-length DA infectious clone persisted and demyelinated similarly to wild-type DA virus (O. van Eyll and T. Michiels, J. Virol. 74:9071-9077, 2000). We now...
Journal of virology, 1999
Although the etiology of multiple sclerosis (MS) is not known, several factors play a role in this disease: genetic contributions, immunologic elements, and environmental factors. Viruses and virus infections have been associated with the initiation and/or enhancement of exacerbations in MS. Theiler's murine encephalomyelitis virus (TMEV) infection of mice is one of the animal models used to mimic MS. In other animal model systems, DNA vaccination has been used to protect animals against a variety of virus infections. To explore the utility of DNA vaccination, we have constructed eukaryotic expression vectors encoding the TMEV capsid proteins VP1, VP2, and VP3. SJL/J mice were vaccinated intramuscularly once, twice, or three times with the different capsid protein cDNAs. This was followed by intracerebral TMEV infection to determine the effects of DNA vaccination on the course of TMEV-induced central nervous system (CNS) demyelinating disease. We found that vaccination of mice t...
Scientific Reports, 2019
epilepsy is a complex neurological disease characterized by recurrent seizures. patients with viral encephalitis have a 16-fold increased risk of developing epilepsy, and this risk can persist for about 15 years after the occurrence of initial viral infection. theiler's murine encephalomyelitis virus (tMeV) infection induces a well-characterized experimental model of epilepsy in C57BL/6 mice. In response to intracerebral (I.C.) injection of Daniel's (DA) strain of tMeV, there is vigorous immune response, which is detrimental to neurons and contributes to acute seizures, rendering mice susceptible to epilepsy. A comparative in vivo challenge study with either one of the two variants of the DA strain, small (DA-D s) or large (DA-C L) plaque forming variants, revealed differences in the diseases they induced in C57BL/6 mice. Compared to DA-C L-, DAD s-infected mice exhibited significantly more seizures, higher clinical scores, neuroinflammation, and neuronal damage (mainly in the CA1-CA2 regions of hippocampus). Moreover, the brains of DAD s infected mice contained approximately five-fold higher virus than those of DA-C L infected mice. A sequence comparison of the DA-C L and DAD s genome sequences showed mutations in the leader (L) and L* proteins of DA-C L variant, which may be the cause of attenuating phenotype of DA-C L variant in the C57BL/6 mouse model of epilepsy. Theiler's murine encephalomyelitis virus (TMEV) is a single stranded RNA virus that belongs to the Picornaviridae family 1. It is found naturally in the enteric system of mice 2,3. TMEV is divided into two serolog-ically related but biologically and neuropathologically distinct subgroups, GDVII and Theiler's original (TO). The GDVII subgroup contains highly neurovirulent GDVII and FA strains, while the TO subgroup contains less neurovirulent DA, BeAn 8386 (BeAn), WW, Yale, and TO4 strains 1,2,4-7. Intracerebral (I.C.) infection with TMEV induces different neurological diseases in mice based upon the virus strain or mouse strain used 1,4,8-15. The GDVII subgroup causes acute fatal polioencephalomyelitis in all strains of mice including SJL mice 4,8 , and acute fatal encephalitis accompanied with seizures in C57BL/6 mice 13,14. DA and BeAn are the two most commonly studied virus strains in the TO subgroup. DA-or BeAn-infected SJL mice develop biphasic disease characterized by early (weeks 1-2 post-infection [p.i.]) mild poliomyelitis and late (~2 months p.i.) demyelinating disease 1,10. In SJL mice, infectious virus is not cleared and persists at low titers, primarily in the spinal cord 1,16-18. In contrast to developing demyelinating disease, DA-or BeAn-infected C57BL/6 mice develop acute (within a week p.i.) seizures 13 that progress into epilepsy after an indefinite latent phase (~1-2 months p.i.) 19. In C57BL/6 mice infectious virus is cleared from the CNS within one month p.i. 20. Interestingly, tonic-clonic seizures or hyperexcitabilty were also observed in FA-, and occasionally in GDVII-infected Swiss mice 8. However, like the SJL mice, DA-infected Swiss mice develop demyelinating disease 9,11. This suggests some phenotypic overlap among the TMEV strains, and among the mouse strains. TMEV subgroups also differ from one another based upon their in vitro characteristics. The GDVII viruses form large plaques (1 to 5 mm), whereas the TO viruses usually form small plaques (0.2-1 mm) on baby hamster kidney (BHK) cells 4,5. Dr. Leibowitz and colleagues observed that their DA strain of TMEV produced a mixture of large and small sized plaques when assayed on L2 cells. The large plaques were 1.51 ± 0.16 mm, while small 1
Susceptibility to Theiler's virus-induced demyelination. Mapping of the gene within the H-2D region
Journal of Experimental Medicine, 1986
Demyelination induced by Theiler's virus was examined in mouse strains with congeneic recombinant haplotypes. Light and electron microscopy of spinal cord sections from mice with s, q, v, p, and f H-2D alleles showed perivascular inflammation and primary demyelination. The presence of susceptible haplotypes in the K or I region did not correlate with pathologic abnormalities. The Qa, Tla, PgK, and UpG genes did not appear to be critical in determining susceptibility to disease. However, mutation in the H-2D genes altered the susceptibility to virus-induced demyelination. B10.D2dm1 mice, which have deletions in the 3' end of Dd and the 5' end of Ld, showed prominent demyelination and clinical deficits. In contrast, BALB/c-dm2, which have a deletion of the entire L gene, showed no pathologic changes. Central nervous system virus titers correlated with susceptibility to demyelination; both resistant and susceptible strains had a strong humoral immune response to the virus. ...
Brain Pathology, 2006
We compared CNS disease following intracere-bral injection of SJL mice with Daniel's (DA) and BeAn 8386 (BeAn) strains of Theiler's murine encephalomyelitis virus (TMEV). In tissue culture, DA was more virulent then BeAn. There was a higher incidence of demyelination in the spinal cords of SJL/J mice infected with DA as compared to BeAn. However, the extent of demyelination was similar between virus strains when comparing those mice that developed demyelination. Even though BeAn infection resulted in lower incidence of demyelination in the spinal cord, these mice showed significant brain disease similar to that observed with DA. There was approximately 100 times more virus specific RNA in the CNS of DA infected mice as compared to BeAn infected mice. This was reflected by more virus antigen positive cells (macrophages/microglia and oligodendrocytes) in the spinal cord white matter of DA infected mice as compared to BeAn. There was no difference in the brain infiltrating immune cells of DA or BeAn infected mice. However, BeAn infected mice showed higher titers of TMEV specific antibody. Functional deficits as measured by Rotarod were more severe in DA infected versus BeAn infected mice. These findings indicate that the diseases induced by DA or BeAn are distinct.