Functional analysis of Epstein-Barr Virus genome variation in relation to cell growth and disease

EB 病毒基因组变异与细胞生长和疾病相关的功能分析

• 批准号: MR/N010388/1
• 负责人: Paul Farrell
• 金额: $ 78.3万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN010388%2F1
• 关键词: Functional; analysis; Epstein; Barr; Virus

Most people are infected by Epstein-Barr virus (EBV) as young children, and carry the virus for their whole life with no ill effects, but the virus can cause several human diseases. Glandular fever occurs when people who were not infected as children first become infected with EBV as teenagers or adults. Also, several specific types of cancer are caused by EBV; together these cancers account for 1.5% of all human cancers worldwide. EBV may also play a role in multiple sclerosis. These diseases occur at quite different rates in different parts of the world and we suspect that the different EBV strains present in those parts of the world may be part of the reason for that. We therefore need to understand what variation is actually present in EBV strains and find out whether it makes a difference to function of the virus, in ways that might be relevant to the human diseases associated with EBV. We have recently published the first large scale DNA sequencing of EBV from different parts of the world, and from various EBV-cancers. This application will make use of this new information to understand how the variation in EBV sequence has an impact on EBV biology. In fact, we now know that most EBV research so far has used EBV lab strains that are poor representatives of the viruses that circulate in the human population. We shall therefore isolate - in a pure form suitable for research - a set of diverse EBV strains and assess their characteristics. The viruses will be tested by infection of human cells relevant to the diseases, both in the lab and in an animal model.We shall also test two specific examples of the impact of virus diversity on biology and disease that have been highlighted by our preliminary work. First we shall investigate how two of the EBV genes (called EBNA2 and EBNA3) work together to determine the much greater ability of certain EBV strains to cause growth of white blood cells, likely relevant to some of the blood cancers associated with EBV. Second, we shall test whether specific differences we have identified in Chinese EBV may help to explain the very high incidence of EBV associated nasopharyngeal cancer that occurs in Hong Kong and nearby parts of China.

大多数人在年幼时就感染了EB病毒（EBV），并且终生携带该病毒而没有不良影响，但该病毒可导致多种人类疾病。腺热发生在儿童时期未感染的人在青少年或成年时首次感染EBV。此外，几种特定类型的癌症是由EBV引起的;这些癌症占全球所有人类癌症的1.5%。EBV也可能在多发性硬化症中发挥作用。这些疾病在世界不同地区的发生率相当不同，我们怀疑世界上这些地区存在的不同EBV毒株可能是其中的部分原因。因此，我们需要了解EBV毒株中实际存在的变异，并找出它是否会以可能与EBV相关的人类疾病相关的方式对病毒的功能产生影响。我们最近发表了来自世界不同地区和各种EBV癌症的第一个大规模EBV DNA测序。该应用程序将利用这些新信息来了解EBV序列中的变异如何对EBV生物学产生影响。事实上，我们现在知道，到目前为止，大多数EBV研究都使用了EBV实验室毒株，这些毒株不能很好地代表在人群中传播的病毒。因此，我们将分离-在一个纯的形式适合研究-一组不同的EBV株，并评估其特性。我们将在实验室和动物模型中，通过感染与疾病相关的人类细胞来测试病毒。我们还将测试我们前期工作中强调的病毒多样性对生物学和疾病影响的两个具体例子。首先，我们将研究两个EBV基因（称为EBNA 2和EBNA 3）如何共同作用，以确定某些EBV毒株引起白色血细胞生长的能力更强，这可能与某些与EBV相关的血癌有关。其次，我们将测试我们在中国EBV中发现的特定差异是否有助于解释香港和中国附近地区EBV相关鼻咽癌的高发病率。

项目成果

The Cooperative Functions of the EBNA3 Proteins Are Central to EBV Persistence and Latency.

• DOI: 10.3390/pathogens7010031
• 发表时间: 2018-03-17
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Styles CT;Paschos K;White RE;Farrell PJ
• 通讯作者: Farrell PJ

A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection.

• DOI: 10.1371/journal.ppat.1007179
• 发表时间: 2018-07
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Bristol JA;Djavadian R;Albright ER;Coleman CB;Ohashi M;Hayes M;Romero-Masters JC;Barlow EA;Farrell PJ;Rochford R;Kalejta RF;Johannsen EC;Kenney SC
• 通讯作者: Kenney SC

Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naïve B cells, and facilitates recruitment of transcription factors to the viral genome.

• DOI: 10.1371/journal.ppat.1006890
• 发表时间: 2018-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Szymula A;Palermo RD;Bayoumy A;Groves IJ;Ba Abdullah M;Holder B;White RE
• 通讯作者: White RE

Requirement for PRC1 subunit BMI1 in host gene activation by Epstein-Barr virus protein EBNA3C.

Epstein-Barr 病毒蛋白 EBNA3C 激活宿主基因时需要 PRC1 亚基 BMI1。

• DOI: 10.1093/nar/gky1323
• 发表时间: 2019
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Paschos K

Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA.

• DOI: 10.1128/jvi.00375-17
• 发表时间: 2017-08-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Correia S;Palser A;Elgueta Karstegl C;Middeldorp JM;Ramayanti O;Cohen JI;Hildesheim A;Fellner MD;Wiels J;White RE;Kellam P;Farrell PJ
• 通讯作者: Farrell PJ