Blocking RNA virus replication through the antiviral functions of cellular helicases

 描述(申请人提供)：通过细胞解旋酶的抗病毒功能阻止RNA病毒复制。先天免疫中一个新出现的概念是细胞固有限制因子(CIRF)对几种病毒的重要作用，其表达方式为 宿主细胞。CIRF极大地减少了病毒的复制，有助于对抗病毒，并使诱导的和被动的先天免疫反应更加有效。PI已经确定细胞死盒解旋酶是针对RNA病毒的强大的CIRF。RNA解旋酶参与细胞代谢的方方面面，执行RNA双链解离和细胞内RNA-蛋白质复合体的重塑。剖析细胞解旋酶的抗病毒作用机制有望为开发针对植物和动物病毒的有效抗病毒策略提供新的途径。番茄丛矮病毒和酵母模型等易于处理的病毒-宿主系统的使用极大地促进了我们对宿主因素机制的理解。PI将识别和表征最有效的细胞解旋酶来阻止植物和昆虫病毒的复制。该提案将重点放在两个显示出最有效的抗病毒作用的细胞解旋酶上，从而证明这一新方法的潜力。以下是该提议的主要优点：(I)病毒RNA复制显然对病毒感染活的生物体具有极其重要的作用。(Ii)目前研究宿主因子参与病毒RNA复制和病毒致病机制最有效的方法是用酵母和正宗的无细胞试验相结合的方法。(Iii)细胞解旋酶正在成为对几种病毒的主要细胞内在限制因素(Iv)这项工作有可能获得一种新的有效的抗病毒方法，该方法具有几个优于传统病毒靶点的优点。其优势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效果，以及更持久的抗病毒效果。在这个优雅的番茄病毒-酵母系统中，开发一种基于通过细胞螺旋阻断病毒复制的有效抗病毒策略可以迅速完成。基于这些从植物到动物高度保守的细胞解旋酶可能具有的广泛抗病毒作用，研究人员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。这项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方面取得突破性成果，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.