Genetic Analysis of Signaling Components in Innate Immunity

先天免疫信号成分的遗传分析

• 批准号: 7670122
• 负责人: David E Levy
• 金额: $ 23.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670122
• 关键词: Adjuvant; Antiviral Agents; Antiviral resistance; Area; Attenuated; Biochemical; Cell Line; Cells; Chikungunya virus; Collaborations; Critical Pathways; Cytoplasm; Data; Dendritic Cells; Development; Diagnostic; Effectiveness; Elements; Equilibrium; Gene Expression; Genetic; Human; Immune; Immune system; Immunity; Impairment; Infection; Influenza; Influenza A virus; Interferon Inducers; Interferon Type I; Interferons; Knowledge; Lesion; Mediating; Mission; Molecular; Mus; Natural Immunity; Nature; Nucleic Acids; Outcome; Pathogenesis; Pathway interactions; Proteins; Research; Signal Pathway; Signal Transduction; Staging; System; Toll-like receptors; Vaccines; Vaccinia; Vaccinia virus; Viral; Virulence; Virulence Factors; Virus; Virus Diseases; Virus Inhibitors; Work; base; biodefense; drug discovery; gene induction; genetic analysis; immune resistance; inhibitor/antagonist; member; microbial; novel strategies; novel therapeutics; pressure; receptor; response; small molecule; therapeutic target; viral resistance

Type I interferon (IFN) provides an initial component of innate immune resistance to viral infection and replication by inducing a large set of antiviral effector proteins capable of inhibiting diverse viruses at multiple points in the infection. Inherent to the effectiveness of this response are cellular signaling pathways that first trigger IFN gene induction in response to infection and subsequently trigger IFN-stimulated gene (ISG) expression in response to secreted IFN. IFN gene induction proceeds through two distinct pathways, a cytosolic signaling system triggered by viral nucleic acid in the cytoplasm that operates in most infected cells and a transmembrane pathway dependent on Toll-like receptor (TLR) proteins that is critical in dendritic cells. The essential nature of the IFN system in antiviral immunity has been demonstrated by genetic and biochemical data, but its ultimate effectiveness is limited by viral evasion through the action of viral virulence factors that impaire IFN action. The underlying hypothesis of our proposed research is that through better understaning the molecular mechanisms of IFN induction and action and their impairment by viral evasion, we will be able to devise novel therapeutics based on augmenting innate immunity and inhibiting viral evasion. This project focuses on three distinct viruses that each impair the IFN pathway, influenza A virus, vaccinia virus, and chikungunya virus; will analyze the interaction between viruses and IFN signaling in a unique set of genetically modified dendritic cells lines; and will develop a platform to screen for small molecule inhibitors of viral virulence. This work will be performed in close collaboration with other members of the innate immunity team, Drs. Easier, Garcia-Sastre, and Wu. This project is well integrated into the mission of the RCE. Innate immunity has emerged as an essential component of the key focus areas of the RCE, impacting on adaptive immunity and being critical for athe adjuvant effects of vaccines; providing an important diagnostic indication of infection; and uncovering a novel approach to therapeutics by targeting the interaction between the innate immune system and virulence factors. Knowledge gained in these studies will also be applicable to microbial innate immunity that relies on similar mechani

I 型干扰素 (IFN) 提供了对病毒感染和复制的先天免疫抵抗力的初始组成部分 通过诱导大量抗病毒效应蛋白，能够在体内多个点抑制多种病毒 感染。这种反应有效性的本质是首先触发 IFN 基因的细胞信号传导途径 诱导响应感染，并随后触发 IFN 刺激基因 (ISG) 表达以响应 分泌干扰素。 IFN 基因诱导通过两种不同的途径进行，一种是由以下物质触发的胞质信号系统： 细胞质中的病毒核酸在大多数感染细胞中发挥作用，跨膜途径依赖于 Toll 样受体 (TLR) 蛋白在树突状细胞中至关重要。干扰素系统抗病毒的本质 免疫力已被遗传和生化数据证明，但其最终有效性受到病毒的限制 通过损害 IFN 作用的病毒毒力因子的作用来逃避。我们提出的基本假设 研究的重点是通过更好地了解干扰素诱导和作用的分子机制及其作用 病毒逃避造成的损害，我们将能够设计出基于增强先天免疫和 抑制病毒逃避。该项目重点关注三种不同的病毒，每种病毒都会损害 IFN 途径：甲型流感 病毒、牛痘病毒和基孔肯雅病毒；将以独特的方式分析病毒和 IFN 信号传导之间的相互作用 一组转基因树突状细胞系；并将开发一个筛选病毒小分子抑制剂的平台 毒力。这项工作将与先天免疫团队的其他成员密切合作进行。 更容易，加西亚-萨斯特雷和吴。 该项目很好地融入了 RCE 的使命。先天免疫已成为一种重要的 RCE 关键重点领域的组成部分，影响适应性免疫并对佐剂至关重要 疫苗的影响；提供重要的感染诊断指征；并发现一种新颖的方法 通过针对先天免疫系统和毒力因子之间的相互作用进行治疗。获得的知识 这些研究也将适用于依赖类似机制的微生物先天免疫