A chikungunya Viral Replicon as a Platform for Antiviral Therapeutics

基孔肯雅病毒复制子作为抗病毒治疗的平台

• 批准号: 8789899
• 负责人: David E Levy
• 金额: $ 29.91万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-31 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789899
• 关键词: Adjuvant; Antiviral Agents; Antiviral resistance; Area; Biochemical; Cell Line; Cells; Chikungunya virus; Collaborations; Cytoplasm; Data; Dendritic Cells; Development; Diagnostic; Effectiveness; Gene Expression; Genetic; Immune system; Immunity; Impairment; Infection; Influenza A virus; Interferon Type I; Interferons; Knowledge; Mission; Molecular; Natural Immunity; Nature; Nucleic Acids; Pathway interactions; Proteins; Replicon; Research; Signal Pathway; Signal Transduction; System; Therapeutic; Toll-like receptors; Vaccines; Vaccinia virus; Viral; Virulence; Virulence Factors; Virus; Virus Diseases; Virus Inhibitors; Work; adaptive immunity; base; biodefense; chikungunya; drug discovery; gene induction; immune resistance; member; microbial; novel strategies; novel therapeutics; receptor; response; small molecule; therapeutic target

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 mechanisms.

I型干扰素（IFN）通过诱导大量抗病毒效应蛋白，在感染的多个点抑制多种病毒，为先天免疫抵抗病毒感染和复制提供了初始成分。这种反应的有效性所固有的是细胞信号通路，它首先触发IFN基因诱导以应对感染，随后触发IFN刺激基因（ISG）表达以应对分泌的IFN。IFN基因诱导通过两种不同的途径进行，一种是由细胞质中的病毒核酸触发的胞质信号系统，在大多数感染细胞中起作用，另一种是依赖于toll样受体（TLR）蛋白的跨膜途径，在树突状细胞中至关重要。遗传和生化数据已经证明了IFN系统在抗病毒免疫中的基本性质，但其最终有效性受到病毒通过损害IFN作用的病毒毒力因子的作用而逃避的限制。我们提出的研究的基本假设是，通过更好地了解IFN诱导和作用的分子机制以及病毒逃避对它们的损害，我们将能够设计基于增强先天免疫和抑制病毒逃避的新疗法。该项目侧重于三种不同的病毒，每种病毒都损害干扰素通路，即甲型流感病毒、牛痘病毒和基孔肯雅病毒；将分析一组独特的转基因树突状细胞系中病毒和干扰素信号之间的相互作用；并将开发一个平台来筛选病毒毒力的小分子抑制剂。这项工作将与先天免疫小组的其他成员密切合作进行。放松点，加西亚·萨斯特和吴。