Role of TRIM79 in innate immunity to tick-borne encephalitis virus

TRIM79 在蜱传脑炎病毒先天免疫中的作用

• 批准号: 8611898
• 负责人: Roger Travis Taylor
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-05 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611898
• 关键词: Accounting; Address; Adopted; Amino Acid Sequence; Antiviral Agents; Antiviral Response; Binding; Binding Proteins; Biological Assay; Cell physiology; Containment; Data; Dengue Virus; Detection; Drug usage; Effectiveness; Engineering; Equilibrium; Flavivirus; Flavivirus Infections; Genes; Goals; Health; Human; Immune; Immune response; Individual; Infection; Interferon Type I; Interferons; Knowledge; Measures; Mediating; Modeling; Molecular; Molecular Virology; Mutation; Natural Immunity; Peptide Sequence Determination; Peptides; Point Mutation; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Process; Property; Proteins; Reagent; Research; Resistance; Role; Scanning; Signal Pathway; Signal Transduction; Structure; TRIM Family; TRIM Gene; Text; Therapeutic; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Training; Viral; Viral Proteins; Virulent; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; abstracting; attenuation; base; burden of illness; design; experience; fitness; gene function; in vivo; inhibitor/antagonist; insight; member; mimetics; novel strategies; protein degradation; research study; response; small molecule; therapeutic development; vaccine candidate

DESCRIPTION (provided by applicant): Abstract PI: TAYLOR, ROGER TRAVIS Project: 1K22AI099020-01 Title: Role of TRIM79 in innate immunity to tick-borne encephalitis virus Accession Number: 3398464 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== The flaviviruses represent a tremendous disease burden to humans, including dengue virus, West Nile virus (WNV) and tick-borne encephalitis virus (TBEV). These viruses are highly sensitive to the antiviral effects of type I interferon (IFN). However, the effectiveness of IFN asa therapeutic is limited by the ability of these viruses to inhibit IFN-dependent signal transduction and therefore dampen the expression of IFN-stimulated genes (ISGs). ISGs are responsible for the antiviral effects of IFN, although little is known regarding the function of individual gene products. A molecular understanding of virus-specific antiviral molecules is needed to define how host interferon (IFN) responses are effective against virus infections. Although many ISGs function as general inhibitors of virus infection, ISGs necessary for protection against specific viruses exist, evolved to selectively target unique viral protein sequences. Members of the TRIM family of proteins are emerging as potent but virus-specific detection and antiviral factors, in addition to regulators of innate immune signal pathways. Our work has identified a virus-specific TRIM protein, TRIM79, as an ISG that binds the NS5 protein from tick-borne encephalitis virus (TBEV) and targets it for degradation, resulting in virus restriction. TRIM79 was not able to bind to NS5 from the closely related West Nile virus (WNV), nor restrict WNV replication. Thus, the TRIM79/NS5 interaction represents a unique model to explore the molecular and cellular determinants required for protein recognition and degradation as well as restriction of viruses directly relevant to human health on a global scale. The overall goal of this work is to identify mechanisms of specific virus restriction by cellular antiviral molecules by dissecting apart the TRIM79/NS5 relationship, insight from which will enable identification of other antiviral molecules with similar mechanisms. We will accomplish this goal by identifying the structural and functional determinants for both TRIM79 and NS5 necessary for binding, protein degradation and subsequent virus restriction. Insight gained from initial studies will be used to rationally engineer mutations into the NS5 from flaviviruses either resistant (TBEV) or susceptible (WNV) to TRIM79- mediated restriction and measure effect of mutation on virus replication and interferon sensitivity. These studies will define the role of TRIM79 for TBEV restriction, as well as normal cellular functions. Flaviviruses, including TBEV, WNV and DENV, account for an overwhelming worldwide disease burden, with limited treatment options. A mechanistic understanding of how a single TBEV-specific antiviral gene that is central to the innate antiviral response will enable development of therapeutics effective against flaviviruses evolved to specifically disable IFN-dependent signal transduction.

描述（由申请人提供）： 摘要 PI：Taylor，Roger Travis 项目：1 K22 AI 099020 -01标题：TRIM 79在蜱传脑炎病毒先天免疫中的作用登录号：3398464 ================== 注意事项：本摘要摘自应用程序，未经SRA验证。当应用程序扫描过程出现问题时，提取的文本可能不正确或不完整。 ================== 黄病毒属对人类造成巨大的疾病负担，包括登革热病毒、西尼罗河病毒（WNV）和蜱传脑炎病毒（TBEV）。这些病毒对I型干扰素（IFN）的抗病毒作用高度敏感。然而，IFN阿萨治疗剂的有效性受到这些病毒抑制IFN依赖性信号转导的能力的限制 从而抑制干扰素刺激基因（ISG）的表达。ISG负责IFN的抗病毒作用，尽管关于单个基因产物的功能知之甚少。需要对病毒特异性抗病毒分子的分子理解来确定宿主干扰素（IFN）应答如何有效对抗病毒感染。尽管许多ISG作为病毒感染的一般抑制剂起作用，但存在针对特定病毒的保护所必需的ISG，其进化为选择性地靶向独特的病毒蛋白质序列。TRIM蛋白家族的成员正在成为除了先天免疫信号通路的调节剂之外的有效但病毒特异性的检测和抗病毒因子。我们的工作已经确定了一种病毒特异性TRIM蛋白，TRIM 79，作为一种ISG，它结合来自蜱传脑炎病毒（TBEV）的NS 5蛋白，并靶向其降解，导致病毒限制。TRIM 79不能与来自密切相关的西尼罗河病毒（WNV）的NS 5结合，也不能限制WNV复制。因此，TRIM 79/NS 5相互作用代表了一种独特的模型，可以在全球范围内探索蛋白质识别和降解以及限制与人类健康直接相关的病毒所需的分子和细胞决定因素。这项工作的总体目标是通过解剖TRIM 79/NS 5关系来确定细胞抗病毒分子对特定病毒限制的机制，从中可以识别具有类似机制的其他抗病毒分子。我们将通过鉴定TRIM 79和NS 5结合、蛋白降解和随后的病毒限制所必需的结构和功能决定因素来实现这一目标。从初步研究中获得的见解将用于合理地将突变工程化到来自对TRIM 79介导的限制性酶切具有抗性（TBEV）或敏感性（WNV）的黄病毒的NS 5中，并测量突变对病毒复制和干扰素敏感性的影响。这些研究将确定TRIM 79对TBEV限制以及正常细胞功能的作用。黄病毒，包括TBEV，WNV和DENV，占压倒性的全球疾病负担，治疗选择有限。对作为先天性抗病毒反应中心的单个TBEV特异性抗病毒基因的机制理解将使得能够开发有效对抗黄病毒的治疗剂，所述黄病毒进化为特异性地使IFN依赖性信号转导失效。