Mechanism of IFIT-Mediated Antiviral Effects

IFIT 介导的抗病毒作用机制

• 批准号: 8836291
• 负责人: JAMES P WHITE
• 金额: $ 5.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836291
• 关键词: Affect; Animal Model; Antiviral Agents; Antiviral Response; Binding; Biochemical; Biological Assay; Biological Models; C57BL/6 Mouse; Cell Culture Techniques; Cell Nucleus; Cells; Cessation of life; Complement; Complex; Culicidae; Cytoplasm; Data; Development; Encephalitis; Enzymes; Eukaryota; Eukaryotic Cell; Eukaryotic Initiation Factor-3; Family; Flavivirus; Genes; Goals; Guanosine; Homo; Human; Hydroxyl Radical; Immune; Immune response; In Vitro; Individual; Infection; Interferon Type I; Interferons; Knock-out; Knockout Mice; Laboratories; Ligands; Mediating; Messenger RNA; Methylation; Methyltransferase; Modeling; Modification; Molecular Virology; Mus; Nuclear Export; Pathogenesis; Point Mutation; Positioning Attribute; Protein Family; Proteins; RNA; RNA Binding; RNA Caps; RNA analysis; RNA replication; RNA, Messenger, Splicing; Reaction; Relative (related person); Research Personnel; Ribose; Role; Series; Structure; Tissues; Training; Transcript; Translation Initiation; Translations; Vertebrates; Viral; Virus; Virus Diseases; West Nile virus; Work; base; biochemical model; biophysical model; career; cell type; genomic RNA; in vivo; innate immune function; member; mouse model; mutant; novel; novel vaccines; pathogen; prevent; protein complex; public health relevance; response; tripolyphosphate; viral RNA

 DESCRIPTION (provided by applicant): Viral infection induces the activation of the innate immune and Type I interferon responses, which act to restrict viral replication and spread. West Nile virus (WNV) is an emerging mosquito-borne pathogen that can cause fatal encephalitis in multiple vertebrate animal species. In the majority of cases, activation of the cell-intrinsic and cell-extrinsic innate immune responses controls viral replication and prevents encephalitis and death. Understanding the mechanisms by which WNV infection is inhibited by the innate immune response requires an understanding of the antiviral functions of innate immune proteins induced by infection. In this proposal, we will characterize the antiviral action of an evolutionarly conserved family of proteins termed interferon-induced protein with tetratricopeptide repeats (IFIT). IFIT proteins are induced early and to high levels during an innate immune response and have been shown to recognize viral RNA as non-self due to the presence of atypical RNA modifications at the 5' end; however, the mechanism by which this recognition occurs and the role of individual IFIT proteins in recognizing viral RNA has yet to be determined. Here, we will use biochemical and cell-culture based assays to determine the ability of IFIT proteins to bind viral RNA and determine how RNA binding and recognition inhibits viral replication. We also will use a mouse model lacking all three Ifit genes to assess tissue- and cell-type-specific effects of IFIT antiviral activity. We hypothesize that different combinations of IFIT proteins will differentially affect viral replication and that IFIT proteins will show a tissue- and cell type-specific dominance. The results of this study may support the use of viruses from multiple families that are highly susceptible to IFIT antiviral activity as novel vaccines and provide an avenue for development of novel antiviral agents that sensitize viruses to the antiviral effects of IFIT proteins.

 描述（由申请方提供）：病毒感染诱导先天免疫和I型干扰素应答的激活，其作用是限制病毒复制和传播。西尼罗河病毒（WNV）是一种新出现的蚊媒病原体，可导致多种脊椎动物致命的脑炎。在大多数情况下，细胞内在和细胞外在先天免疫应答的激活控制病毒复制并预防脑炎和死亡。了解先天免疫反应抑制西尼罗河病毒感染的机制需要了解感染诱导的先天免疫蛋白的抗病毒功能。在这个建议中，我们将描述一个进化上保守的蛋白质家族的抗病毒作用，称为干扰素诱导蛋白与tetratricopeptide重复序列（IFIT）。IFIT蛋白在先天性免疫应答期间被早期诱导并达到高水平，并且由于在5'端存在非典型RNA修饰，已显示将病毒RNA识别为非自身;然而，这种识别发生的机制以及单个IFIT蛋白在识别病毒RNA中的作用尚未确定。在这里，我们将使用生物化学和细胞培养为基础的测定，以确定IFIT蛋白结合病毒RNA的能力，并确定如何RNA的结合和识别抑制病毒复制。我们还将使用缺乏所有三个Ifit基因的小鼠模型来评估IFIT抗病毒活性的组织和细胞类型特异性效应。我们假设IFIT蛋白的不同组合将差异影响病毒复制，IFIT蛋白将显示组织和细胞类型特异性优势。这项研究的结果可能支持使用来自多个家族的对IFIT抗病毒活性高度敏感的病毒作为新型疫苗，并为开发新型抗病毒药物提供了一条途径，这些药物可使病毒对IFIT的抗病毒作用敏感。 IFIT蛋白。