Foot-and-mouth disease virus entry: RNA release and membrane penetration

口蹄疫病毒进入：RNA 释放和膜渗透

• 批准号: BB/H018301/1
• 负责人: Tobias Tuthill
• 金额: $ 58.94万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH018301%2F1
• 关键词: Foot; mouth; disease; virus; entry

Foot-and-mouth disease virus (FMDV) is one of the most important pathogens affecting agricultural livestock. It is endemic in much of the world, especially in the developing world where its presence restricts the ability to export animal products to disease free countries and so adversely affects rural economies. The virus is one of the most infectious agents known and its ability to cause economic and social havoc was amply demonstrated by the outbreak in the UK in 2001 which cost the country ~£10 billion. FMDV is a member of the picornavirus family which includes other viruses such as poliovirus and rhinovirus (the common cold virus). One of the least well understood steps in the infection process by this family of viruses is how the virus particle is 'uncoated' and transports its genetic material (the blueprint for new virus) across the cell membrane to initiate an infection. We have been studying this process, in collaboration with other laboratories, using poliovirus (PV), which is the best understood of all picornaviruses. From this work, a model of how the infection process is achieved by PV is slowly evolving. It appears to be an elegant and sophisticated mechanism involving a series of intermediate particles. However, FMDV particles are known to have very different properties to those of PV and appear to behave differently during the infection process and this makes it difficult to extrapolate the PV model to FMDV. We intend to apply the novel techniques that we have developed in recent years for studying PV to investigate in detail the mechanism of cell entry by FMDV. These methods use artificial lipid membrane structures to mimic cellular membranes in such a way that they can be finely controlled and examined in the laboratory. We will attempt to mimic the infectious process using these systems and examine the intermediate structures formed during the uncoating of the virus and their effects on the properties of the membranes themselves. In this way we hope to gain insight into how the virus uncoats and projects its RNA genome across an artificial equivalent of a cell membrane. Although these studies are of immediate academic interest, a better understanding of the infection process may also have more practical value in the longer term. For example, alterations in virus structure during the infection process may expose new targets for improved diagnosis of the disease or for the development of vaccines or antiviral drugs to block infection, as has been shown for HIV.

口蹄疫病毒（Foot-and-mouth disease virus，FMDV）是影响农业家畜的重要病原之一。它在世界许多地方流行，特别是在发展中国家，它的存在限制了向无病国家出口动物产品的能力，从而对农村经济产生不利影响。该病毒是已知的最具传染性的病原体之一，其造成经济和社会破坏的能力在2001年英国爆发的疫情中得到了充分证明，该疫情使该国损失了约100亿英镑。口蹄疫病毒是小核糖核酸病毒家族的一员，该家族还包括其他病毒，如脊髓灰质炎病毒和鼻病毒（普通感冒病毒）。在这个病毒家族的感染过程中，最不为人所知的步骤之一是病毒颗粒如何“未被包裹”并将其遗传物质（新病毒的蓝图）穿过细胞膜以启动感染。我们一直在与其他实验室合作，使用脊髓灰质炎病毒（PV）研究这一过程，这是所有小核糖核酸病毒中最好的理解。从这项工作中，一个如何通过PV实现感染过程的模型正在慢慢发展。这似乎是一个优雅而复杂的机制，涉及一系列中间粒子。然而，已知FMDV颗粒具有与PV非常不同的性质，并且在感染过程中表现出不同的行为，这使得难以将PV模型外推到FMDV。我们打算应用我们近年来开发的研究PV的新技术来详细研究FMDV进入细胞的机制。这些方法使用人工脂质膜结构来模拟细胞膜，以便在实验室中对其进行精细控制和检查。我们将尝试使用这些系统来模拟感染过程，并检查在病毒脱壳过程中形成的中间结构及其对膜本身性质的影响。通过这种方式，我们希望能够深入了解病毒如何将其RNA基因组剥离并投射到人工等效的细胞膜上。虽然这些研究具有直接的学术意义，但从长远来看，更好地了解感染过程也可能具有更大的实用价值。例如，在感染过程中病毒结构的改变可能会暴露新的靶标，用于改进疾病的诊断或用于开发疫苗或抗病毒药物以阻断感染，如HIV所示。

项目成果

Capsid protein VP4 of human rhinovirus induces membrane permeability by the formation of a size-selective multimeric pore.

• DOI: 10.1371/journal.ppat.1004294
• 发表时间: 2014-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Panjwani A;Strauss M;Gold S;Wenham H;Jackson T;Chou JJ;Rowlands DJ;Stonehouse NJ;Hogle JM;Tuthill TJ
• 通讯作者: Tuthill TJ

Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes.

• DOI: 10.1371/journal.ppat.1006197
• 发表时间: 2017-02
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Groppelli E;Levy HC;Sun E;Strauss M;Nicol C;Gold S;Zhuang X;Tuthill TJ;Hogle JM;Rowlands DJ
• 通讯作者: Rowlands DJ

Structures of foot and mouth disease virus pentamers: Insight into capsid dissociation and unexpected pentamer reassociation.

• DOI: 10.1371/journal.ppat.1006607
• 发表时间: 2017-09
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Malik N;Kotecha A;Gold S;Asfor A;Ren J;Huiskonen JT;Tuthill TJ;Fry EE;Stuart DI
• 通讯作者: Stuart DI