REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15

最近爆发的高致病性流感病毒突显了需要一种 更好地了解流感病毒与其宿主之间的相互作用。病毒式传播 感染触发迅速的抗病毒反应，I型干扰素(IFN)发挥作用 在协调宿主反应中的中心作用，通过上调一个大的 干扰素刺激基因数(ISGs)。几种ISG具有直接的抗病毒活性， 而另一些则通过调节免疫系统来影响抗病毒反应。我们 最近发现其中一种ISG，ISG15，作为一种关键的干扰素诱导 抗病毒分子。ISG15是一种被IFN强烈上调的泛素同系物， Toll受体连接和病毒感染。ISG15缺陷小鼠的致死率增加 在感染了几种病毒后，包括甲型和乙型流感病毒。然而， ISG15发挥这种抗病毒活性的机制尚不清楚。ISG15偶联物 以多种生物过程为靶标的一系列细胞内蛋白质。 人类ISG15也从细胞中释放出来，并作为细胞因子发挥作用，激活各种 免疫细胞。在这个提议中，我们将检验ISG15的共轭 靶向蛋白质可抑制呼吸道内的病毒复制 这种病毒可以在皮肤上皮细胞上皮细胞中传播，并允许宿主随后清除病毒。我们将测试 这一假设有以下两个目的。目标1中的研究将探索 ISG15调节呼吸道上皮内病毒复制的机制。 我们还将确定ISG15在这种细胞类型中的表达是否足以控制 流感病毒感染。目标2中的研究将确定ISG15的接合是否 ISG15的抗病毒活性所需的。我们将确定ISG15是否与 病毒蛋白和调节病毒复制。从这些研究中获得的结果将 提供重要的洞察力，了解新确定的 抗病毒分子，ISG15。ISG15是一种关键的抗病毒分子，对几种 人类病原体，包括甲型和乙型流感病毒。这项提议将 通过调查探讨其在流感病毒感染中的作用机制 它的作用视线和与靶蛋白质结合的要求。这些 研究可能为这场斗争中潜在的新治疗靶点提供洞察力 对抗病毒感染。

Recent outbreaks of highly pathogenic influenza virus have highlighted the need for a better understanding of the interactions between influenza virus and its host. Viral infection triggers a prompt anti-viral response, with type I interferons (IFNs) playing the central role in coordinating the host response through the upregulation of a large number of IFN stimulated genes (ISGs). Several ISGs have direct antiviral activity, while others impact upon the antiviral response by modulating the immune system. We have recently shown that one of these ISGs, ISG15, functions as a critical IFN induced anti-viral molecule. ISG15 is an ubiquitin homolog that is strongly upregulated by IFNs, toll receptor ligation, and viral infection. ISG15 deficient mice display increased lethality following infection with several viruses, including both influenza A and B viruses. Yet the mechanism by which ISG15 exerts this antiviral activity is unknown. ISG15 conjugates to a wide array of intracellular proteins, targeting numerous biological processes. Human ISG15 is also released from cells and functions as a cytokine, activating various immune cells. In this proposal we will test the hypothesis that the conjugation of ISG15 to target proteins results in the inhibition of viral replication within the respiratory epithelium and allows for subsequent clearance of the virus by the host. We will test this hypothesis with the following two aims. The studies in Aim 1 will explore the mechanism by which ISG15 regulates viral replication within the respiratory epithelium. We will also determine if expression of ISG15 within this cell type is sufficient to control influenza virus infection. The studies in Aim 2 will determine if conjugation of ISG15 is required for the antiviral activity of ISG15. We will determine if ISG15 conjugates to viral proteins and regulates viral replication. The results obtained from these studies will provide important insight into a potential mechanism of action for a newly identified antiviral molecule, ISG15. ISG15 functions as a critical antiviral molecule, with activity against several human pathogens, including both influenza A and B viruses. This proposal will explore its mechanism of action during influenza virus infection by investigating its sight of action and requirement for conjugation to target proteins. These studies may provide insight into a potential new therapeutic target in the fight against viral infections.