The pathogenesis of virus-induced disease is complex with many host-, cell-, and pathogen specific determinants. A general theme of this proposal is the importance of viral RNA translational regulation and cell-type specific RNA binding proteins in determining picornavirus-induced disease. Our studies involve Theiler's murine encephalomyelitis virus (TMEV), a member of the cardiovirus genus, and poliovirus (PV), a member of the enterovirus genus. Our main interests in this proposal are: neural cell type-specific proteins which bind to the internal ribosome entry site (IRES) of the 5'- untranslated region (UTR), and thereby regulate the efficiency of translation initiation and affect TMEV or PV neurovirulence; preferential translation of an alternatively initiated protein of TMEV called L* (a protein synthesized from an alternative translation initiation site that is out of frame with the polyprotein, a unique finding among picornaviruses), that is important in virus persistence and demyelination of DA strain of TMEV. This proposal: reviews and extends our published data demonstrating that the presence of cell type-specific proteins that bind the internal ribosome entry site (IRES) of the 5'-UTR of GDVII strain of TMEV are key in regulating viral RNA translation and neurovirulence; provides recent data indicating the importance of cell type-specific IRES-binding proteins in the attenuation of Sabin strain of PV3; focuses on the importance of L* in determining the remarkable phenotype of DA strain and other TO subgroup strains of TMEV (i.e., virus persistence and chronic inflammatory demyelination). The data and approaches that are leaned in this proposal are applicable to our understanding of neurotrophic viruses more broadly.
The specific aims are: 1) To identify determinants in the TMEV and PV 5'UTRs that regulate translation and affect disease phenotype, and clarify their mechanisms of action 2) To: a) identify the effect of cell type on the expression of TMEV L*, and b) determine the effect of TMEV gene expression on the cell.
