Characterization of the mode of antiviral action of IRG 1

I型干扰素(IFN)反应保护细胞免受病毒病原体的入侵。调节这种防御的细胞因素是干扰素刺激基因(ISGs)的产物。尽管自发现以来已经发现了数百个ISGs，但只有少数几个被描述为具有抗病毒活性。对于大多数ISG产品，人们对它们的抗病毒潜力、靶标特异性和作用机制知之甚少。不同的ISG被认为对不同的病毒家族具有更强的抗病毒活性。此外，一些ISG可能是细胞类型受限的，与在特定组织中抑制病毒更相关。钻石实验室利用神经细胞功能获得/功能丧失分析，确定ISG免疫相关GTPase(IRG)1是一种潜在的抗病毒因子，可对抗包括西尼罗河病毒(WNV)和其他正链RNA病毒在内的嗜神经性病毒。IRG1属于RAS-型GTP酶家族，其中GTP部分作为生化开关。然而，IRG1发挥其抗病毒作用的机制目前尚不清楚。因此，这项研究计划的目的是通过以下方式获得对IRG1特异性抗病毒效应功能的新见解：(1)表征它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依赖的抗病毒反应的影响。这一信息可用于随后帮助确定IRG1的特定抗病毒作用机制。(2)确定其对几种嗜神经和其他正/负链RNA病毒的抗病毒潜力和靶标特异性。随着钻石集团开发的新产生的IRG1-/-小鼠的上市，将测试其对不同病毒组的抗病毒作用的程度。此外，还将研究IRG1在抗病毒免疫中的细胞类型贡献。临床上，干扰素被用来治疗多种病毒感染，是乙肝和丙型肝炎病毒治疗的主要成分。考虑到干扰素治疗的临床副作用，以及病毒对其信号和活性的天然拮抗能力，利用单个ISGs的作用可能是一种更好的治疗策略。对这些效应器的生化机制的进一步了解可能为开发干扰素治疗的替代方案提供平台。

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.