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型干扰素提供对病毒感染和复制的先天免疫抵抗的初始成分 通过诱导大量的抗病毒效应蛋白能够在体内的多个点抑制不同的病毒 感染。这种反应的有效性所固有的是首先触发干扰素基因的细胞信号通路 诱导对感染的应答并随后触发干扰素刺激基因(ISG)的表达 分泌型干扰素。干扰素基因的诱导通过两条不同的途径进行，胞质信号系统由 在大多数感染细胞中运行的细胞质中的病毒核酸和依赖于 在树突状细胞中起关键作用的Toll样受体(TLR)蛋白。干扰素系统在抗病毒中的本质 免疫力已被遗传和生化数据证明，但其最终效果受到病毒的限制。 通过削弱干扰素作用的病毒毒力因子的作用而逃避。我们提出的基本假设是 研究表明，通过更好地了解干扰素的诱导和作用的分子机制以及它们的 通过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，每种病毒都会破坏干扰素途径，即甲型流感 病毒、牛痘病毒和基孔肯雅病毒；将分析病毒之间的相互作用和干扰素信号在一个独特的 一套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 致命性。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，还有吴。 该项目很好地融入了区域经济委员会的使命。先天免疫力已经成为一种必不可少的 RCE关键焦点区域的组成部分，影响获得性免疫，对佐剂至关重要 疫苗的效果；提供感染的重要诊断指征；以及揭示一种新的方法 通过靶向天然免疫系统和毒力因子之间的相互作用进行治疗。学到的知识 这些研究也将适用于依赖类似机制的微生物先天免疫。