VIRAL INHIBITION OF HOST DEFENSES

宿主防御的病毒抑制

• 批准号: 6196471
• 负责人: David J Pickup
• 金额: $ 34.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6196471
• 关键词: Poxviridae; apoptosis; chick embryo; cytokine; cytokine receptors; host organism interaction; immunoprecipitation; laboratory mouse; laboratory rabbit; microarray technology; microorganism immunology; nuclear factor kappa beta; nucleic acid sequence; open reading frames; phenotype; posttranslational modifications; protease inhibitor; protein purification; protein structure function; proteolysis; serine proteinases; site directed mutagenesis; tissue /cell culture; tumor necrosis factor alpha; virus genetics; virus infection mechanism; virus protein

The long-term goal of this study is to identify mechanisms of viral inhibition of host immune defenses against infection. The poxvirus family includes some of the most virulent of all human pathogens. In part, the pathogenicity of these viruses results from their abilities to counter host defenses against infection. Cowpoxvirus, a virus closely related to smallpoxvirus, encodes about two hundred proteins, many of which are involved in the inhibition of immune processes. In particular, this virus effectively inhibits inflammatory processes. Because of these properties, it provides a unique system for investigation of these processes. This system has already enabled us to identify seven viral cytokine-response modifiers: CrmA, an inhibitor of several caspases and granzyme B: a soluble, interleukin-1 receptor; soluble, secreted, TNF receptors of three types: CrmB, CrmC, and CrmD; a soluble, secreted receptor for beta-chemokines; a soluble, secreted receptor for the CD30 ligand. His results suggest that cowpox virus encodes numerous additional cytokine-response modifiers and inhibitors affecting both non-specific and specific immune defenses. In particular, he has found that poxviruses inhibit the activation of NF-kB, a transcription factor of cardinal importance in a wide range of immune and pathological processes. The immediate specific aims of this study are as follows: (1) To determine the mechanisms by which poxviruses inhibit the activation of NF-kB. (2) To identify additional mechanisms employed by cowpoxvirus to counter immune responses. (3) To determine the mechanism of gene expression-dependent uncoating of poxviruses. Knowledge of the mechanisms involved in the effective poxviral inhibition of host defenses against infection should assist the development of new therapies for a variety of conditions associated with infectious diseases, inflammatory diseases, autoimmune diseases, cancers, and organ transplantation.

这项研究的长期目标是确定 病毒抑制宿主对感染的免疫防御。痘病毒家族 包括一些最致命的人类病原体。部分地 这些病毒的致病性来自它们对抗宿主的能力 防止感染。牛痘病毒，一种与 天花病毒编码大约200种蛋白质，其中许多蛋白质与 免疫过程的抑制。特别是，这种病毒有效地 抑制炎症过程。由于这些属性， 独特的系统来研究这些过程。该系统已经 使我们能够确定七种病毒性丝氨酸反应调节剂：CrmA， 几种半胱天冬酶和颗粒酶B抑制剂：可溶性白细胞介素-1 受体;三种类型的可溶性分泌型TNF受体：CrmB、CrmC和 β-趋化因子的可溶性分泌型受体 CD 30配体的受体。他的研究结果表明牛痘病毒编码 许多另外的干扰素反应调节剂和抑制剂影响 非特异性和特异性免疫防御。他特别发现， 痘病毒抑制NF-κ B的激活，NF-κ B是一种主要的转录因子， 在广泛的免疫和病理过程中的重要性。 本研究的直接具体目的如下：（1）确定 痘病毒抑制NF-κ B活化的机制。(2)以识别 牛痘病毒对抗免疫反应的其他机制。（三） 为了确定基因表达依赖性脱膜的机制， 痘病毒了解痘病毒有效治疗的机制 抑制宿主对感染的防御应该有助于 用于与传染病相关的各种病症的新疗法， 炎性疾病、自身免疫性疾病、癌症和器官移植。