BASIS FOR THE IFP PHENOTYPE OF DIABETOGENIC EMC VIRUS

脑心肌炎（EMC）病毒诱导的糖尿病， 小鼠在以下方面与青少年发病糖尿病的一个子集相似： 人类 两个其他类似的变种来自M- EMC病毒株可用于研究，其 干扰素诱导颗粒（IFP）表型和它们 导致小鼠糖尿病。 EMC-B变体是ifp+， 感染小鼠的循环干扰素（IFN）水平， 胰岛的有限感染，并且不引起糖尿病。 当循环IFN被抗IFN球蛋白中和时， 糖尿病是由EMC-B感染引起的，这表明 干扰素系统，可能是ifp表型，是一个决定因素， 糖尿病的结果。 EMC-D变体为ifp-， 循环干扰素水平，破坏胰岛， 糖尿病小鼠 关键的遗传差异必须负责 这些密切相关的病毒的不同生物学特性。 为了确定这些特性的遗传基础，我们 已经克隆了对应于完整开放阅读的cDNA 两种变体的框架。 他们的限制性内切酶图谱是 对12种不同的酶来说都是一样的 另外，前103个核苷酸 在基因组的5'端的非翻译RNA的 一模一样 我们建议发现IFP的遗传基础 EMC病毒表型和致糖尿病性的初步比较 B和D变体的完整核苷酸序列。 的 核苷酸序列差异的功能意义， 在开放阅读帧中发生的 通过参考RNA的体外翻译产物， 转录本和EMC病毒蛋白的已知功能。 将合成B和D变体的完整cDNA， 哺乳动物细胞的转染。 关于差异 在开放阅读框内或外的核苷酸序列中， 将合成B和D的嵌合分子。 生物 重组病毒的特性将被确定， 来独立地确定导致 IFP表型和致糖尿病性。 这些知识将进一步 我们对病毒毒力和致病机制的理解 病毒诱导干扰素。 使用此提供的数据 项目，它可能是预测人类的毒力 病毒遗传结构的知识。

Encephalomyocarditis (EMC) virus induced diabetes mellitus in mice has similarities to a subset of juvenile onset diabetes in humans. Two otherwise similar variants derived from the M- strain 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 infection 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 the different biological properties of these closely related viruses. In order to determine the genetic basis for these properties we have cloned cDNA corresponding to the complete open reading frame of both variants. Their restriction endonuclease maps are identical for 12 different enzymes. Also, the first 103 nucleotides of the untranslated RNA at the 5' end of the genomes are identical. We propose to discover the genetic basis for the ifp phenotype and diabetogenicity of EMC virus by first comparing the complete nucleotide sequences of the B and D variants. The functional significance of differences in nucleotide sequence that are found to occur in the open reading frame will be ascertained by reference to the in vitro translation products of RNA transcripts and to the known functions of EMC viral proteins. Complete cDNA of the B and D variants will be synthesized for transfection of mammalian cells. With reference to differences in nucleotide sequence within or outside the open reading frame, chimeric molecules of B and D will be synthesized. The biological properties of the recombinant viruses will be determined in order to independently determine the genetic locus responsible for the ifp phenotype and diabetogenicity. This knowledge will further our understanding of virus virulence and the mechanism of interferon induction by viruses. Using data provided by this project, it may be possible to predict the virulence of human viruses from a knowledge of genetic structure.