Characterization of the mode of antiviral action of IRG 1

IRG 1 抗病毒作用模式的表征

• 批准号: 266373065
• 负责人: Dr. Sharmila Nair, Ph.D.
• 金额: --
• 依托单位: Division of Infectious Diseases
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/266373065?language=en
• 关键词: Characterization; mode; antiviral; action; IRG

The type I interferon (IFN) response protects cells against invading viral pathogens. The cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Different ISGs are thought to have more potent antiviral activities toward different families of viruses. Additionally, some ISGs may be cell-type restricted and be more relevant for inhibiting a virus in specific tissues.Using gain of function/loss of function assays in neuronal cells, the Diamond lab identified the ISG- Immunity related GTPase (Irg) 1 as a potential antiviral factor against neurotropic viruses including West Nile virus (WNV) and other positive-strand RNA viruses. Irg1 belongs to the family of Ras-type GTPase where the GTP moiety serves as a biochemical switch. However, the mechanism by which Irg1 executes its antiviral effect currently remains unknown. Thus, the aim of this research proposal is to gain novel insights into Irg1 specific antiviral effector functions by:(1) Characterizing which stage of the West Nile replication cycle it restricts. The effect of the GTPase domain on Irg1 dependent antiviral responses will also be investigated. This information can be used subsequently to help define the specific antiviral mechanism of action of Irg1.(2) Determining its antiviral potential and target specificity against several neurotropic and other positive/ negative stranded RNA viruses. With the availability of the newly generated Irg1-/- mice developed by the Diamond group, the extent of its antiviral action against different virus groups will be tested. Moreover, the cell-type contribution of Irg1 to antiviral immunity also will be investigated. Clinically, IFN is used to treat several viral infections and is a principle component of Hepatitis B and Hepatitis C virus treatment. Given the clinical side effects of IFN treatment, and the natural ability of viruses to antagonize its signaling and activity, exploiting the actions of individual ISGs may be a preferable therapeutic strategy. Further insight into the biochemical mechanisms of these effectors may provide a platform for the development of alternatives to IFN-based therapies.

I 型干扰素 (IFN) 反应可保护细胞免受病毒病原体的入侵。介导这种防御的细胞因子是干扰素刺激基因（ISG）的产物。尽管自发现以来已鉴定出数百种 ISG，但只有少数 ISG 具有抗病毒活性。对于大多数 ISG 产品，人们对其抗病毒潜力、靶标特异性及其作用机制知之甚少。不同的 ISG 被认为对不同的病毒家族具有更有效的抗病毒活性。此外，一些 ISG 可能受细胞类型限制，并且与抑制特定组织中的病毒更相关。通过对神经元细胞进行功能获得/功能丧失测定，Diamond 实验室确定 ISG-免疫相关 GTP 酶 (Irg) 1 是针对嗜神经病毒（包括西尼罗河病毒 (WNV) 和其他正链 RNA 病毒）的潜在抗病毒因子。 Irg1 属于 Ras 型 GTP 酶家族，其中 GTP 部分充当生化开关。然而，Irg1 发挥抗病毒作用的机制目前仍不清楚。因此，本研究计划的目的是通过以下方式获得对 Irg1 特异性抗病毒效应子功能的新见解：(1) 表征其限制西尼罗河复制周期的哪个阶段。还将研究 GTPase 结构域对 Irg1 依赖性抗病毒反应的影响。该信息随后可用于帮助确定 Irg1 的特定抗病毒作用机制。(2) 确定其抗病毒潜力和针对几种神经性病毒和其他正链/负链 RNA 病毒的靶标特异性。随着 Diamond 小组开发的新产生的 Irg1-/- 小鼠的上市，将测试其针对不同病毒组的抗病毒作用程度。 此外，还将研究 Irg1 对抗病毒免疫的细胞类型贡献。临床上，干扰素用于治疗多种病毒感染，是乙型肝炎和丙型肝炎病毒治疗的主要组成部分。考虑到 IFN 治疗的临床副作用，以及病毒拮抗其信号传导和活性的天然能力，利用单个 ISG 的作用可能是一种更好的治疗策略。进一步深入了解这些效应器的生化机制可能为开发基于 IFN 的疗法的替代方案提供平台。