Key result
High DA L-coding expression triggers fatal paralysis and myelin cell death in transgenic mice.
Expression of the DA L-coding region of TMEV directly causes dysfunction and death of myelin-synthesizing cells, suggesting a direct viral role in demyelinating diseases.
Indicates L-region dose determines oligodendrocyte fate in mice; leaves open relevance to human demyelinating disease.
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 transient weakness with demyelination and persistent expression of the recombined transgene. These findings demonstrate that a high level of expression of DA L can cause the death of myelin-synthesizing cells and death of the mouse, while a lower level of L expression (which can persist) can lead to cellular dysfunction with survival. The results suggest that expression of DA L plays an important role in the pathogenesis of TMEV-IDD. Virus-induced infection and death of oligodendrocytes may play a part in the demyelination of other diseases in which an immune-mediated mechanism has been stressed, including multiple sclerosis.
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Ghadge et al. (2011) studied TMEV-induced demyelinating disease. Tamoxifen-induced expression of the DA L-coding region was evaluated on Development of paralysis, cellular abnormalities, and demyelination. High-level expression of the DA L-coding region in transgenic mice caused death of myelin-synthesizing cells and fatal paralysis, while lower expression led to cellular dysfunction and survival.
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