Testing novel anti-viral strategies in plants

在植物中测试新型抗病毒策略

• 批准号: BB/L022095/1
• 负责人: Peter Stockley
• 金额: $ 58.08万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL022095%2F1
• 关键词: Testing; novel; anti; viral; strategies

Single-stranded (ss) RNA viruses are major pathogens, and factors such as climate change and increased mobility mean that new viruses of this type will emerge more frequently, presenting enormous societal challenges. These viruses infect plants and cause severe reductions in crop yields. They also infect livestock, and the recent UK outbreak of Foot & Mouth Disease Virus illustrates the potentially devastating effects they can have on the agricultural economy. Other viruses will become common UK pathogens because their vectors, mostly biting insects, are becoming more widespread. Viruses are thus a significant threat to efforts to expand and secure world food supply. Despite their importance, few solutions for viral infection exist beyond vaccination, which is not possible for plant viruses, and novel strategies are therefore urgently required. We are proposing to test here several novel anti-viral strategies that target the assembly and disassembly stage of the viral life cycle, and are based on our unique insights into the mechanisms of assembly and disassembly in ssRNA viruses. Our recent work has transformed our understanding of virus assembly, i.e. the process of surrounding the viral RNA genome with a protective shell made of viral coat protein sub-units. We have shown that the efficient construction of these essential transport vehicles depends critically on multiple short sequences within the viral RNA, termed packaging signals (PSs), and their interactions with the viral coat protein sub-units. We have defined and identified the roles of PSs in a wide range of ssRNA viruses, and are proposing to extend this work here to a carefully chosen selection of model ssRNA plant viruses. We will determine the cooperative impact of groups of PSs on capsid assembly in these viruses and test strategies to interfere with efficient capsid formation via expression of decoy RNAs targeting PS activity.Moreover, we will exploit the importance of specific capsid components in disassembly and infection. ssRNA viruses have been intensively studied, and the highly-symmetric structures of their protective protein capsids are well understood. However, successes in structural virology mask a fundamental problem: many of these viruses are not truly icosahedral. They have unique, non-symmetric components that are essential to their biology, including their genomes, but these are generally missing from structural models that use symmetry averaging. These unique components are absolutely essential to virus biology, because they allow viruses to respond dynamically to their environment and transform a stable, protective structure into one that is primed to release its genetic information into a cell and start an infection.

单链（ss）RNA病毒是主要病原体，气候变化和流动性增加等因素意味着此类新病毒将更频繁地出现，带来巨大的社会挑战。这些病毒感染植物并导致农作物产量严重下降。它们还会感染牲畜，最近英国爆发的口蹄疫病毒说明了它们可能对农业经济造成的潜在破坏性影响。其他病毒将成为英国常见的病原体，因为它们的载体（主要是叮咬昆虫）正变得更加广泛。因此，病毒对扩大和确保世界粮食供应的努力构成重大威胁。尽管它们很重要，但除了疫苗接种之外，几乎没有什么解决病毒感染的方法，而这对于植物病毒来说是不可能的，因此迫切需要新的策略。我们提议在此测试几种针对病毒生命周期的组装和解组装阶段的新型抗病毒策略，并且基于我们对 ssRNA 病毒组装和解组装机制的独特见解。我们最近的工作改变了我们对病毒组装的理解，即用由病毒外壳蛋白亚基组成的保护壳包围病毒 RNA 基因组的过程。我们已经证明，这些重要运输工具的有效构建关键取决于病毒 RNA 内的多个短序列（称为包装信号 (PS)）及其与病毒外壳蛋白亚基的相互作用。我们已经定义并鉴定了 PS 在多种 ssRNA 病毒中的作用，并提议将这项工作扩展到精心挑选的模型 ssRNA 植物病毒。我们将确定 PS 组对这些病毒中衣壳组装的协同影响，并测试通过表达针对 PS 活性的诱饵 RNA 来干扰有效衣壳形成的策略。此外，我们将利用特定衣壳成分在分解和感染中的重要性。 ssRNA病毒已被深入研究，其保护性蛋白衣壳的高度对称结构已被充分了解。然而，结构病毒学的成功掩盖了一个基本问题：许多病毒并不是真正的二十面体。它们具有对其生物学（包括基因组）至关重要的独特的非对称成分，但使用对称平均的结构模型通常缺少这些成分。这些独特的成分对于病毒生物学来说绝对重要，因为它们使病毒能够动态地响应其环境，并将稳定的保护性结构转变为准备将其遗传信息释放到细胞中并开始感染的结构。

项目成果

Rewriting nature's assembly manual for a ssRNA virus.

• DOI: 10.1073/pnas.1706951114
• 发表时间: 2017-11-14
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Patel N;Wroblewski E;Leonov G;Phillips SEV;Tuma R;Twarock R;Stockley PG
• 通讯作者: Stockley PG

Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2.

• DOI: 10.1016/j.jmb.2015.11.014
• 发表时间: 2016-01-29
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Rolfsson Ó;Middleton S;Manfield IW;White SJ;Fan B;Vaughan R;Ranson NA;Dykeman E;Twarock R;Ford J;Kao CC;Stockley PG
• 通讯作者: Stockley PG

Bacteriophage MS2 genomic RNA encodes an assembly instruction manual for its capsid.

• DOI: 10.1080/21597081.2016.1157666
• 发表时间: 2016-01
• 期刊: Bacteriophage
• 作者: Stockley PG;White SJ;Dykeman E;Manfield I;Rolfsson O;Patel N;Bingham R;Barker A;Wroblewski E;Chandler-Bostock R;Weiß EU;Ranson NA;Tuma R;Twarock R
• 通讯作者: Twarock R