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抗性的初始组成部分 通过诱导大量抗病毒效应子蛋白，能够抑制多个点的多种病毒 感染。该反应有效性固有的是首次触发IFN基因的细胞信号通路 响应感染，随后触发了IFN刺激的基因（ISG）表达，以响应于 分泌的ifn。 IFN基因诱导通过两种不同的途径进行，这是由胞质信号传导系统触发的 在大多数感染细胞和跨膜途径中起作用的细胞质中的病毒核酸 在树突状细胞中至关重要的Toll样受体（TLR）蛋白。 IFN系统在抗病毒中的基本特性 遗传和生化数据已经证明了免疫力，但其最终有效性受病毒的限制 通过损害IFN作用的病毒毒力因子的作用来逃避。我们提议的基本假设 研究是，通过更好地理解IFN诱导和作用的分子机制及其 通过逃避病毒障碍，我们将能够基于增强先天免疫力和 抑制病毒逃避。该项目着重于每个损害IFN途径的三种不同病毒，流感 病毒，牛ac病毒和基孔肯雅病毒；将分析唯一的病毒和IFN信号之间的相互作用 一组转基因的树突状细胞系；并将开发一个平台以筛选病毒的小分子抑制剂 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 - astre和吴。 该项目已很好地整合到了RCE的任务中。先天免疫已成为必不可少的 RCE的关键重点区域的组成部分，影响适应性免疫，对辅助剂至关重要 疫苗的作用；提供感染的重要诊断指示；并发现一种新颖的方法 通过靶向先天免疫系统与毒力因子之间的相互作用来进行治疗。获得的知识 这些研究也将适用于依赖类似机械的微生物先天免疫