ISG15 REGULATION OF ANTIVIRAL IMMUNE RESPONSES

ISG15 抗病毒免疫反应的调节

• 批准号: 7391498
• 负责人: Deborah J Lenschow
• 金额: $ 19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391498
• 关键词: Antigen-Presenting Cells; Antigens; Antiviral Agents; Antiviral Response; Biological Process; Cell Maturation; Cell Proliferation; Cell physiology; Cells; Cercopithecine Herpesvirus 1; Chemotaxis; Data; Defect; Dendritic Cells; Disease Outbreaks; Family; Future; Genes; Goals; Homologous Gene; Human; Immune; Immune response; Immune system; Infection; Influenza; Interferon Type I; Interferons; Investigation; Lead; Leucocytic infiltrate; Ligation; Lung; Molecular; Mus; Natural Killer Cells; Numbers; Postdoctoral Fellow; Production; Proteins; Recombinants; Regulation; Reporting; Serum; Sindbis Virus; Testing; Transgenic Mice; Ubiquitin; Up-Regulation; Viral; Virus; Virus Diseases; Work; base; chemokine; cytokine; influenzavirus; insight; macrophage; neutrophil; receptor; response; virus pathogenesis

DESCRIPTION (provided by applicant): Recent outbreaks of highly pathogenic influenza virus have highlighted the need for a better understanding of the molecular mechanisms of influenza virus pathogenesis and the host immune response to these viruses. Viral infection triggers a prompt anti-viral response, including the release of proinflammatory cytokines from cells such as macrophages and dendritic cells. Type I interferons (IFNs) coordinate the host response by upregulating 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 immune cells including dendritic cells. We have shown that viral infection induces both ISG15 conjugate formation and its release into the serum. We also see a potent proinflammatory cytokine response in ISG15-/- mice following viral infection. Together, these data lead us to the hypothesis that ISG15 regulates the function of dendritic cells during viral infection to modulate the innate, and potentially the adaptive immune response. The goal of this proposal is to test this underlying hypothesis via the follow Aims. The studies in Aim 1 will determine if ISG15 deficient dendritic cells have an intrinsic defect in their response to viral infection. We will evaluate their ability to produce proinflammatory cytokines and function as antigen presenting cells. The studies in Aim 2 will determine if the immune response to viral infection in altered in ISG15 deficient mice. Finally, in Aim 3 we will test the hypothesis that expression of ISG15 in dendritic cells will rescue ISG15-/- mice from lethality. The results obtained from these studies will provide important insight into a potential mechanism of action for a newly identified antiviral molecule, and provide the necessary groundwork for future investigations into ISG15 activity.

描述（由申请人提供）：高度致病性流感病毒的近期暴发强调了需要更好地理解流感病毒发病机理的分子机制以及对这些病毒的宿主免疫反应。病毒感染会触发迅速的抗病毒反应，包括从巨噬细胞和树突状细胞等细胞中释放促炎性细胞因子。 I型干扰素（IFNS）通过上调大量IFN刺激基因（ISGS）来协调宿主响应。几种ISG具有直接的抗病毒活性，而其他ISG通过调节免疫系统对抗病毒反应的影响。我们最近表明，其中一种ISGS，即ISG15，是关键的IFN诱导的抗病毒分子。 ISG15是一种泛素同源物，由IFN，Toll受体连接和病毒感染强烈上调。 ISG15缺乏小鼠在感染多种病毒后，包括流感病毒和B病毒的杀伤力增加。然而，ISG15发挥这种抗病毒活性的机制尚不清楚。 ISG15偶联到各种细胞内蛋白质，靶向许多生物学过程。人ISG15也从细胞中释放出来，并用作细胞因子，激活包括树突状细胞在内的免疫细胞。我们已经表明，病毒感染诱导ISG15结合形成及其释放到血清中。我们还看到病毒感染后ISG15 - / - 小鼠中有效的促炎细胞因子反应。这些数据共同提出了一个假设，即ISG15调节病毒感染过程中树突状细胞的功能，以调节先天性，并可能是适应性免疫反应。该提案的目的是通过以下目标检验这一基本假设。 AIM 1中的研究将确定ISG15缺陷的树突状细胞在对病毒感染的反应中是否具有内在缺陷。我们将评估它们产生促炎细胞因子并充当抗原呈递细胞的能力。 AIM 2中的研究将确定ISG15缺陷小鼠中对病毒感染的免疫反应是否对病毒感染。最后，在AIM 3中，我们将检验以下假设：树突状细胞中ISG15的表达将使ISG15 - / - 小鼠免于致死性。从这些研究中获得的结果将为新鉴定的抗病毒分子的潜在作用机理提供重要的见解，并为将来对ISG15活性进行研究提供必要的基础。