HOST DEFENSE MECHANISMS AGAINST ALPHAVIRUS ENCEPHALITIS

宿主针对甲病毒脑炎的防御机制

• 批准号: 2057371
• 负责人: BETH C LEVINE
• 金额: $ 9.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2057371
• 关键词: SCID mouse; Sindbis virus; antigen antibody reaction; disease /disorder model; encephalitis virus; fusion gene; gene expression; host organism interaction; immunoglobulin genes; infectious encephalitis; laboratory rat; latent virus infection; monoclonal antibody; virus envelope; virus genetics; virus infection mechanism; virus replication

The primary objective of this proposal is to investigate the mechanisms of host defense that are important for recovery from acute viral infections of the CNS, using SIN encephalitis as a model system. This investigation will provide new insights into virus-host interactions and will thereby provide a biologic framework for the development of new therapeutic antiviral strategies. This proposal will focus on understanding the mechanisms by which MAbs to the SIN E2 envelope glycoprotein restrict SIN gene expression in neurons. Based on preliminary findings demonstrating that the E2 envelope glycoprotein upregulates gene expression in neuroblastoma cells and that anti-E2 MAbs that restrict SIN replication enter virally infected neurons, this research proposal will investigate two principal hypotheses: (1) E2 regulates SIN gene expression and anti-E2 MAbs inhibit SIN replication by altering this regulatory effect; and (2) anti-E2 MAbs act intracellulary to inhibit SIN replication. To investigate the first hypothesis, this proposal will analyze (1) the effects of mutations at amino acid position 55 on the regulation of SIN gene expression in neurons and nonneuronal cells; (2) the role of the transmembrane and cytoplasmic domains of E2 in the regulation of SIN gene expression; (3) the effects of anti-E2 MAbs on E2-mediated upregulation of SIN gene expression; and (4) the role of the cytoplasmic domain of E2 in anti-E2 MAb-mediated inhibition of SIN gene expression. To investigate the second hypothesis, recombinant SIN/immunoglobulin (Ig) gene chimeras will be engineered to express intracellular anti-E2 MAbs in different cellular compartments and the effects of expression of anti-E2 MAbs in different neuronal compartments on SIN replication will be determined.

该提案的主要目的是研究机制 对从急性病毒中恢复很重要的宿主防御 中枢神经系统的感染，使用犯罪脑炎作为模型系统。 这 调查将为病毒宿主相互作用和 因此，是否会为开发新的生物学框架提供生物学框架 治疗性抗病毒策略。 该提议将重点放在 了解mabs to sin e2信封的机制 糖蛋白限制神经元中的罪基因表达。 基于 初步发现表明E2信封糖蛋白 上调神经母细胞瘤细胞中的基因表达和抗E2 mABS 限制罪的复制进入病毒感染的神经元，这是 研究建议将研究两个主要假设：（1）E2 调节罪基因表达和抗E2 mAb抑制罪的复制 通过改变这种法规效果； （2）反E2 mabs法 细胞内抑制罪的复制。 调查第一个 假设，该提案将分析（1）突变的影响 氨基酸位置55在调节罪基因表达中的位置 神经元和非神经元细胞； （2）跨膜和 E2的细胞质结构域在罪基因表达的调节中； （3） 抗E2 mABS对E2介导的SIN基因上调的影响 表达; （4）E2的细胞质结构域在抗E2中的作用 mAb介导的sin基因表达的抑制作用。 调查 第二个假设，重组罪/免疫球蛋白（IG）基因嵌合体将 设计以在不同的细胞中表达细胞内抗E2 mAb 隔室和抗E2 mAb在不同的不同 将确定有关罪复制的神经元室。