BASIS FOR DIABETOGENICITY OF ENCEPHALOMYOCARDITIS VIRUS

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Encephalomyocarditis (EMC) virus induced diabetes mellitus in mice is similar to juvenile onset diabetes in humans. Two otherwise similar variants of EMC virus are available for study that differ in their interferon inducing particle (IFP) phenotype and in their ability to cause diabetes in mice. The EMC-B variant is ifp+, produces high levels of circulating interferon (IFN) in infected mice, causes limited destruction of pancreatic islets and does not cause diabetes. When circulating IFN is neutralized by anti-IFN globulins, diabetes results from infection with EMC-B indicating that the interferon system, possibly the IFP phenotype, is a determinant of the diabetic outcome. The EMC-D variant is ifp-, produces lower levels of circulating IFN; destroys pancreatic islets and causes diabetes in mice. Key genetic differences must be responsible for these different biological properties. We propose to examine this question by synthesizing and cloning the cDNA of the B and D variants. Mammalian cells will be transfected with cDNA copies of the genome and the resulting virus will be examined to verify that the basis for the biological differences has been cloned. The B and D genomes will be compared by three techniques: restriction mapping, synthesis of chimeric molecules and analysis of gene products. Portions of the genome in which differences appear to lie will be sequenced and compared in detail. Data gained from this project will provide an understanding of the mechanism of IFN induction by viruses and of the basis for the diabetogenicity of EMC virus.