REGULATION OF INFLUENZA VIRUS INFECTION BY ISG15

ISG15 对流感病毒感染的监管

• 批准号: 8109260
• 负责人: Deborah J Lenschow
• 金额: $ 33.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109260
• 关键词: Antiviral Agents; Antiviral Response; Biological Process; Bone Marrow; Cell Culture Techniques; Cell physiology; Cells; Chimera organism; Disease Outbreaks; Epithelial Cells; Genes; Growth; Homologous Gene; Human; Immune; Immune response; Immune system; Infection; Influenza; Interferon Type I; Interferons; Life Cycle Stages; Ligation; Mus; Mutant Strains Mice; Pathway interactions; Play; Postdoctoral Fellow; Predisposition; Production; Proteins; Recombinants; Regulation; Reporting; Research Proposals; Resistance; Role; Sindbis Virus; Staging; Structure of respiratory epithelium; System; Testing; Ubiquitin; Up-Regulation; Viral; Viral Proteins; Virus; Virus Diseases; Vision; base; cell type; cytokine; fight against; influenzavirus; insight; new therapeutic target; pathogen; public health relevance; receptor; research study; respiratory; response; selective expression; Antiviral Agents; Antiviral Response; Biological Process; Bone Marrow; Cell Culture Techniques; Cell physiology; Cells; Chimera organism; Disease Outbreaks; Epithelial Cells; Genes; Growth; Homologous Gene; Human; Immune; Immune response; Immune system; Infection; Influenza; Interferon Type I; Interferons; Life Cycle Stages; Ligation; Mus; Mutant Strains Mice; Pathway interactions; Play; Postdoctoral Fellow; Predisposition; Production; Proteins; Recombinants; Regulation; Reporting; Research Proposals; Resistance; Role; Sindbis Virus; Staging; Structure of respiratory epithelium; System; Testing; Ubiquitin; Up-Regulation; Viral; Viral Proteins; Virus; Virus Diseases; Vision; base; cell type; cytokine; fight against; influenzavirus; insight; new therapeutic target; pathogen; public health relevance; receptor; research study; respiratory; response; selective expression

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：最近爆发高度致病的流感病毒的爆发强调了需要更好地理解流感病毒与其宿主之间的相互作用。病毒感染引发了迅速的抗病毒反应，I型干扰素（IFN）通过上调大量IFN刺激基因（ISGS）在协调宿主反应中起着核心作用。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，激活各种免疫细胞。在此提案中，我们将检验以下假设：ISG15的结合靶向蛋白质会导致抑制呼吸上皮中病毒复制的抑制，并允许宿主随后清除该病毒。我们将以以下两个目标检验这一假设。 AIM 1中的研究将探索ISG15调节呼吸中皮内病毒复制的机制。我们还将确定在该细胞类型中ISG15的表达是否足以控制流感病毒感染。 AIM 2中的研究将确定ISG15的抗病毒活性是否需要ISG15的结合。我们将确定ISG15是否与病毒蛋白结合并调节病毒复制。从这些研究中获得的结果将为新鉴定的抗病毒分子ISG15的潜在作用机理提供重要的见解。 ISG15充当关键的抗病毒分子，具有对几种人类病原体的活性，包括流感病毒和B病毒。该提案将通过研究其对靶向蛋白质的作用和要求的视力，探索其在流感病毒感染过程中的作用机理。这些研究可能会深入了解抵抗病毒感染的潜在新治疗靶标。公共卫生相关性：ISG15起着关键的抗病毒分子的作用，对几种人类病原体的活性，包括流感病毒和B病毒。该提案将通过研究其对靶向蛋白质的作用和要求的视力，探索其在流感病毒感染过程中的作用机理。这些研究可能会深入了解抵抗病毒感染的潜在新治疗靶标。