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Picornavirus capsid protein VP4: Essential role in cell entry and conserved antiviral target

小核糖核酸病毒衣壳蛋白 VP4：在细胞进入和保守抗病毒靶点中的重要作用

基本信息

批准号：
MR/K020811/1
负责人：
Tobias Tuthill
金额：
$ 65.57万
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：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK020811%2F1
关键词：
Picornavirus capsid protein VP4 Essential

项目摘要

The picornavirus family includes viruses such as human rhinovirus, poliovirus and enterovirus 71. Human rhinovirus (HRV) infects humans more frequently than any other virus and is responsible for approximately 70% of all subclinical respiratory infections (the common cold) which costs the UK £billions every year. Despite decades of research there remains no licensed drug to prevent or reduce infection. Poliovirus (PV) is the subject of an ongoing world-wide eradication campaign but as we reach closer to the final stages of eradication, some experts believe there is an urgent need for additional novel control strategies for the post-eradication era. Enterovirus 71 was until recently only thought to cause a generally mild disease of young children (hand-foot-and-mouth disease). However, in recent years huge outbreaks of EV71 have swept across China and Southeast Asia with cases in the 100,000s including more severe disease and hundreds of child deaths. No vaccine or antiviral is available.Picornaviruses infect cells by hijacking cellular machinery in order to be taken into the cell within an internalised membrane vesicle. For infection to begin, the virus genome (the blueprint for making new virus) must be delivered through the membrane of this vesicle, to reach the cytoplasm, the compartment of the cell where virus replication occurs. The mechanism used by the virus for genome delivery remains unclear. Understanding this process in more detail will provide valuable insights for the development of antiviral agents that interfere with cell entry.The viral genome is contained within a protein coat or capsid. The capsid protects the genome from environmental damage and is also a dynamic structure which plays a crucial role in the cell entry process. Experiments have shown that during cell entry, one of the capsid proteins, VP4, comes out of the virus and interacts with the membrane. Experiments with mutated viruses have confirmed that VP4 is involved in the entry process. We have used model membranes and recombinant VP4 which provide a convenient system for investigating protein-membrane interactions and membrane permeability. We have demonstrated that VP4 is able to interact with liposomes and induce membrane permeability by forming a multimeric pore. We therefore propose that VP4 functions as a membrane pore during cell entry: the 'hole' in the membrane through which the virus genome is delivered into the cytoplasm. We believe that we should study the role of VP4 in more detail in order to develop molecules or drugs that interact with VP4, block its function and prevent infection.

小核糖核酸病毒家族包括病毒如人鼻病毒、脊髓灰质炎病毒和肠道病毒71。人鼻病毒（HRV）比任何其他病毒更频繁地感染人类，并且负责约70%的所有亚临床呼吸道感染（普通感冒），每年花费英国数十亿英镑。尽管经过几十年的研究，仍然没有获得许可的药物来预防或减少感染。脊髓灰质炎病毒（PV）是正在进行的世界范围根除运动的主题，但随着我们接近根除的最后阶段，一些专家认为迫切需要为根除后时代提供额外的新控制策略。直到最近，肠道病毒71才被认为是引起幼儿的一种一般轻微的疾病（手足口病）。然而，近年来，EV 71病毒的大规模爆发席卷了中国和东南亚，病例达10万例，包括更严重的疾病和数百名儿童死亡。小核糖核酸病毒通过劫持细胞机器来感染细胞，以便通过内化的膜囊泡进入细胞。为了使感染开始，病毒基因组（制造新病毒的蓝图）必须穿过囊泡的膜，到达细胞质，细胞质是病毒复制发生的地方。该病毒用于基因组传递的机制仍不清楚。更详细地了解这一过程将为开发干扰细胞进入的抗病毒剂提供有价值的见解。病毒基因组包含在蛋白质外壳或衣壳中。衣壳保护基因组免受环境损害，也是一种动态结构，在细胞进入过程中起着至关重要的作用。实验表明，在进入细胞期间，衣壳蛋白之一VP 4从病毒中出来并与膜相互作用。突变病毒的实验已经证实VP 4参与了进入过程。我们使用了模型膜和重组VP 4，这为研究蛋白质-膜相互作用和膜渗透性提供了一个方便的系统。我们已经证明，VP 4能够与脂质体相互作用，并通过形成多聚体孔诱导膜通透性。因此，我们认为VP 4在细胞进入过程中起着膜孔的作用：膜上的“孔”，病毒基因组通过该孔被递送到细胞质中。我们认为，我们应该更详细地研究VP 4的作用，以便开发与VP 4相互作用的分子或药物，阻断其功能并预防感染。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Membrane interactions and uncoating of Aichi virus, a picornavirus that lacks a VP4

爱知病毒（一种缺乏 VP4 的小核糖核酸病毒）的膜相互作用和脱壳

DOI：
10.1101/2022.01.10.475380
发表时间：
2022
期刊：
影响因子：
0
作者：
Kelly J
通讯作者：
Kelly J

Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication.

DOI：
10.1128/jvi.00217-17
发表时间：
2017-05-01
期刊：
Journal of virology
影响因子：
5.4
作者：
Guedán A;Swieboda D;Charles M;Toussaint M;Johnston SL;Asfor A;Panjwani A;Tuthill TJ;Danahay H;Raynham T;Mousnier A;Solari R
通讯作者：
Solari R

Structure of Ljungan virus provides insight into genome packaging of this picornavirus.

Ljungan 病毒的结构提供了对该小核糖核酸病毒基因组包装的深入了解

DOI：
10.1038/ncomms9316
发表时间：
2015-10-08
期刊：
Nature communications
影响因子：
16.6
作者：
Zhu L;Wang X;Ren J;Porta C;Wenham H;Ekström JO;Panjwani A;Knowles NJ;Kotecha A;Siebert CA;Lindberg AM;Fry EE;Rao Z;Tuthill TJ;Stuart DI
通讯作者：
Stuart DI

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

The conserved N-terminus of human rhinovirus capsid protein VP4 contains membrane pore-forming activity and is a target for neutralizing antibodies.