Blocking RNA virus replication through the antiviral functions of cellular helicases

通过细胞解旋酶的抗病毒功能阻断 RNA 病毒复制

• 批准号: 9021423
• 负责人: PETER NAGY
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-17 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021423
• 关键词: Animal Experimentation; Animals; Antiviral Agents; Area; Biological Assay; Boxing; Cell physiology; Cells; Complex; Human; Immune response; Infection; Insect Viruses; Integration Host Factors; Knowledge; Life; Metabolism; Methods; Modeling; Natural Immunity; Organism; Plant Viruses; Plants; Protein Family; RNA; RNA Helicase; RNA Viruses; RNA replication; Research; Role; Societies; System; Tombusvirus; Viral; Viral Pathogenesis; Virus; Virus Replication; Work; Yeast Model System; Yeasts; base; combat; fighting; frontier; genome-wide analysis; helicase; novel; novel strategies; pathogen; protein complex; public health relevance; replicase; tomato bushy stunt virus; tool; viral RNA; virology; virus host interaction

 DESCRIPTION (provided by applicant): Blocking RNA virus replication through the antiviral functions of cellular helicases. A recently emerging concept in innate immunity is the significant roles of cell-intrinsic restriction factors (CIRFs) against several viruses, which are expressed by the host cells. CIRFs greatly reduce virus replication and facilitate combating viruses and making the induced and passive innate immune responses more potent. The PI has identified cellular DEAD-box helicases as strong CIRFs against an RNA virus. RNA helicases are involved in all aspects of cellular metabolism and perform RNA duplex unwinding and remodeling of RNA-protein complexes in cells. Dissecting the mechanism of antiviral function of cellular helicases promises a new avenue to develop effective antiviral strategies against plant and possibly animal viruses Progress in our understanding of the mechanisms of host factors is greatly accelerated by the use of easily tractable virus - host systems, such as Tomato bushy stunt virus (TBSV) and yeast model. The PI will identify and characterize the most potent cellular helicases to block plant and insect virus replication. The proposal will focus on two cellular helicases that showed the most potent antiviral effect, thus justifying the potential of tis novel approach. The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iii) Cellular helicases are emerging as major cell-intrinsic restriction factors against several viruses (iv) This work has the potential to obtain a novel effective antiviral approach that has several advantages over traditional viral targets. The advantages include broader antiviral effects against many related and possibly even unrelated viruses and more durable antiviral effects. Developing an efficient antiviral strategy based on blocking viral replication via cellular helicass could rapidly be done in this elegant tombusvirus-yeast system. Based on the possible broad antiviral effect of these cellular helicases, which are highly conserved from plants to animals, research can then adapt the gained knowledge and methods for other animal, human and plant viruses. The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication, host-virus interactions and the adaptation of viruses to their hosts.

 描述（由申请人提供）：通过细胞解旋酶的抗病毒功能阻断RNA病毒复制。先天免疫中最近出现的一个概念是细胞内在限制因子（CIRF）对多种病毒的重要作用，这些病毒由 宿主细胞。 CIRF 大大减少了病毒复制，有利于对抗病毒，并使诱导性和被动性先天免疫反应更加有效。 PI 已鉴定出细胞 DEAD-box 解旋酶是对抗 RNA 病毒的强 CIRF。 RNA解旋酶参与细胞代谢的各个方面，并在细胞中执行RNA双链体解旋和RNA-蛋白质复合物的重塑。剖析细胞解旋酶的抗病毒功能机制为开发针对植物和可能的动物病毒的有效抗病毒策略提供了新途径。通过使用易于处理的病毒宿主系统，例如番茄丛矮化病毒（TBSV）和酵母模型，大大加速了我们对宿主因素机制的理解进展。 PI 将鉴定和表征最有效的细胞解旋酶，以阻止植物和昆虫病毒复制。该提案将重点关注两种显示出最有效抗病毒作用的细胞解旋酶，从而证明这种新颖方法的潜力。该提案的主要优点如下： (i) 病毒 RNA 复制对于病毒感染生物体显然至关重要。 (ii) PI 开发的酵母与真实无细胞检测的结合是目前最有效的研究宿主因子参与病毒 RNA 复制和病毒发病机制的机制。 (iii) 细胞解旋酶正在成为针对多种病毒的主要细胞内在限制因子。 (iv) 这项工作有可能获得一种新颖有效的抗病毒方法，该方法与传统病毒靶点相比具有多种优势。其优点包括对许多相关甚至可能不相关的病毒具有更广泛的抗病毒作用，以及更持久的抗病毒作用。在这个优雅的烟草病毒-酵母系统中，可以快速开发出一种基于通过细胞螺旋阻断病毒复制的有效抗病毒策略。基于这些从植物到动物都高度保守的细胞解旋酶可能具有广泛的抗病毒作用，研究可以将所获得的知识和方法应用于其他动物、人类和植物病毒。该研究有望在病毒复制、宿主与病毒相互作用以及病毒对宿主的适应等领域取得突破性成果，从而造福社会。