Blocking RNA virus replication through the antiviral functions of cellular helicases

 描述（由申请方提供）：通过细胞解旋酶的抗病毒功能阻断RNA病毒复制。最近在先天免疫中出现的概念是细胞内在限制因子（CIRF）针对几种病毒的重要作用，其通过以下方式表达： 宿主细胞CIRFs极大地减少病毒复制，促进对抗病毒，并使诱导的和被动的先天免疫应答更有效。PI已将细胞DEAD盒解旋酶鉴定为针对RNA病毒的强CIRFs。RNA解旋酶参与细胞代谢的各个方面，并在细胞中进行RNA双链体解旋和RNA-蛋白质复合物的重塑。研究细胞解旋酶的抗病毒作用机制，为开发有效的抗植物病毒和动物病毒的抗病毒策略提供了新的途径。利用易于处理的病毒-宿主系统，如番茄丛矮病毒（Tomato bushy stunt virus，TBSV）和酵母模型，大大加快了我们对宿主因子作用机制的理解。PI将鉴定和表征阻断植物和昆虫病毒复制的最有效的细胞解旋酶。该提案将集中在两个细胞解旋酶，显示出最有效的抗病毒作用，从而证明了这种新方法的潜力。以下是该建议的主要优点：（i）病毒RNA复制显然对病毒感染生物体至关重要。(ii)PI开发的酵母和真实无细胞测定法的组合是目前研究宿主因子参与病毒RNA复制和病毒发病机制的最有效方法。(iii)细胞解旋酶正在成为针对几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的有效的抗病毒方法，该方法与传统的病毒靶点相比具有几个优点。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。通过细胞螺旋体阻断病毒复制，开发有效的抗病毒策略可以在这种优雅的番茄丛矮病毒-酵母系统中快速完成。基于这些细胞解旋酶可能具有广泛的抗病毒作用，这些解旋酶从植物到动物都是高度保守的，因此研究可以将所获得的知识和方法用于其他动物、人类和植物病毒。该研究有望通过在病毒复制，宿主-病毒相互作用和病毒适应宿主领域取得突破性成果而造福社会。

 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.