DA and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) group induce a persistent infection, with a restricted virus gene expression, associated with chronic inflammatory demyelination of the spinal cord. Evidence suggests that the immune system contributes to this demyelination;however, persistence of the virus in glia and macrophages is also necessary. This virus-induced immune-mediated demyelinating disease serves as an experimental model of multiple sclerosis (MS) since both processes have similar inflammatory white matter pathology that is believed to be fostered by the immune system. The relative contribution of the DA virus infection of oligodendrocytes vs. immune-mediated damage to the pathogenesis of the white matter disease remains unclear, as is also the case with other demyelinating diseases, including MS. In addition, the mechanisms by which virus genes induce the demyelinating disease remain to be clarified. This NOT-OD-09-056 competitive revision application of R01 NS037958-11 focuses on investigations of DA leader (L) and its relationship to DA-induced demyelinating disease. We have recently published data showing that transgenic mice (called DA/Cre) that inducibly express a subgenomic region of DA that includes the 5'-untranslated region (UTR) and coding regions for the L, L*, and P1 (the capsid proteins) in myelinating cells develop white matter pathology;this study demonstrated that a direct effect of DA virus RNA or a DA virus gene product without an inflammatory infiltrate can mediate the white matter disease. We have now prepared a transgenic mouse (called DAL/Cre) that inducibly expresses DA L (and no other viral genes) in myelin-synthesizing cells. DAL/Cre has a similar phenotype to DA/Cre mice, suggesting that L leads to toxicity of myelin- synthesizing cells. We plan to characterize this mouse and begin to clarify the mechanism by which L causes toxicity of this cell type. We suspect that L is toxic because of its known interference with host cell translation;interestingly, translation defects underlie other non-viral causes of demyelination. We will test whether L interferes with host cell translation in varied neural cell types, including myelin- synthesizing cells of DAL/Cre mice, and whether this interference occurs at the time of dysfunction and death of myelin-synthesizing cells. We will also test whether L expression leads to the expression of various cytokines.
Certain strains of Theiler's virus (TV) induce a chronic inflammatory demyelinating disease that serves as an excellent model of multiple sclerosis. The study of the TV model is an especially attractive and powerful one for pathogenesis studies because of the molecular tools and mouse genetic models that are available. An understanding of the determinants of the TV disease may be valuable in clarifying the mechanisms involved in viral- and non-viral-induced central nervous system disease (such as multiple sclerosis).
