How does Chikungunya virus regulate the switch between genome translation and replication?
基孔肯雅病毒如何调节基因组翻译和复制之间的转换?
基本信息
- 批准号:MR/Y013107/1
- 负责人:
- 金额:$ 102.78万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2024
- 资助国家:英国
- 起止时间:2024 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Chikungunya virus (CHIKV) is an arbovirus, transmitted by Aedes aegypti and Aedes albopictus mosquitos. Since its re-emergence in 2004, it has caused numerous epidemics across expanding geographical ranges within sub-/tropical areas of Africa, Asia and the Americas and increasingly across temperate regions of Europe, Asian and North America. The main risk factor for spread of CHIKV is change in global mosquito vector distribution - as a consequence of climate change associated seasonal variations and increasing mean temperatures, globalisation and changes in land use. Invasive populations of Ae. albopictus have been identified in the UK and temperature rises are expected to increase their months of activity and range.Chikungunya disease is associated with severe debilitating joint pain for months or years and exacerbation of co-morbidities. High mortality rates are observed among elderly patients with pre-existing conditions, such as hypertension or diabetes. Despite increasing numbers of epidemics and their expanding geographical spread, there remains no specific antiviral therapy or licenced vaccine.The mechanism and interactions by which CHIKV controls translation and replication of its genome are unclear. We have shown that CHIKV requires host protein MSI2 to replicate its genome in human cells. We and others have also shown that host protein DHX9 is required for efficient CHIKV translation, while simultaneously inhibiting replication of the virus genome. We demonstrated that MSI2 and DHX9 interact specifically with the 5' region of the CHIKV genome and identified an MSI2 RNA binding site within this region of the virus genome. We previously published a study demonstrating that the 5' region of the virus genome forms complex RNA structures, essential for CHIKV replication. We have also produced preliminary data consistent these RNA structures regulating the MSI2 binding to the CHIKV genome. Therefore, the scientific objective of the project is to generate a detailed functional and structural model of how these different factors interact, to regulate CHIKV translation and genome replication.We will address the following objectives: (i) We will identify MSI2 and DHX9 RNA binding sites within the CHIKV genome and the role of RNA structure in MSI2 and DHX9 binding. (ii) Confocal imaging will be used to determine changes in localisation, co-localisation, expression and degradation of MSI2, DHX9 and nsPs during CHIKV translation and genome replication. Using the same approach, we will determine the influence of individual RNA structures on these changes and interactions. (iii) Our previously published studies demonstrate that RNA structures in the 5' region of the CHIKV genome are essential for virus genome replication. Therefore, we will use in vitro and in cell approaches to determine the RNA structure of the CHIKV genome following interaction with MSI2 and DHX9. We will also determine the RNA structure specifically associated with CHIKV genome replication and different stages of virus translation. (iv) To complete our understanding of the interactions between MSI2, DHX9 and the 5' region of CHIKV genome we use Cryo Electron Microscopy to generate high-resolution 3D models of unbound and protein-bound RNA tertiary structures. With results from the other aims, this will allow us to produce a detailed model of the regulation of CHIKV translation and genome replication.As well as furthering our understanding of how CHIKV controls translation and replication of its genome, results will provide a model for related human pathogenic viruses. An increased understanding of this fundamental mechanism will provide insight towards novel therapeutic targets and attenuated vaccine design.
基孔肯雅病毒是一种虫媒病毒,由埃及伊蚊和白纹伊蚊传播。自2004年重新出现以来,它在非洲、亚洲和美洲的亚热带地区以及欧洲、亚洲和北美的温带地区日益扩大的地理范围内造成了许多流行病。CHIKV传播的主要风险因素是全球蚊媒分布的变化--这是气候变化相关的季节变化和平均气温上升、全球化和土地利用变化的结果。Ae.的入侵种群。白纹伊蚊已经在英国被发现,气温上升预计会增加它们几个月的活动和范围。基孔肯雅病与几个月或几年的严重衰弱关节疼痛有关,并加剧共病。在有高血压或糖尿病等既往疾病的老年患者中观察到高死亡率。尽管流行病的数量不断增加,其地理传播范围也在扩大,但仍然没有专门的抗病毒疗法或获得许可的疫苗。CHIKV控制其基因组翻译和复制的机制和相互作用尚不清楚。我们已经证明CHIKV需要宿主蛋白MSI2在人类细胞中复制其基因组。我们和其他人还表明,宿主蛋白DHX9是有效翻译CHIKV所必需的,同时抑制病毒基因组的复制。我们证明了MSI2和DHX9与CHIKV基因组的5‘端区域特异地相互作用,并在病毒基因组的这一区域内发现了MSI2 RNA结合位点。我们之前发表的一项研究表明,病毒基因组的5‘端形成了复杂的RNA结构,对CHIKV的复制至关重要。我们还产生了与这些调节MSI2与CHIKV基因组结合的RNA结构一致的初步数据。因此,该项目的科学目标是建立一个详细的功能和结构模型,了解这些不同因素是如何相互作用的,以调控CHIKV的翻译和基因组复制。我们将解决以下目标:(I)我们将确定CHIKV基因组中的MSI2和DHX9 RNA结合部位,以及RNA结构在MSI2和DHX9结合中的作用。(Ii)共聚焦成像将被用来确定在CHIKV翻译和基因组复制过程中MSI2、DHX9和NSPS的定位、共定位、表达和降解的变化。使用同样的方法,我们将确定单个RNA结构对这些变化和相互作用的影响。(Iii)我们先前发表的研究表明,CHIKV基因组5‘端的RNA结构是病毒基因组复制所必需的。因此,我们将使用体外和细胞内的方法来确定CHIKV基因组在与MSI2和DHX9相互作用后的RNA结构。我们还将确定与CHIKV基因组复制和病毒翻译不同阶段特定相关的RNA结构。(4)为了更好地理解MSI2、DHX9与CHIKV基因组5‘端的相互作用,我们使用低温电子显微镜建立了非结合和蛋白质结合的RNA三级结构的高分辨率三维模型。根据其他目标的结果,这将使我们能够产生一个详细的模型来调控CHIKV的翻译和基因组复制,并进一步了解CHIKV如何控制其基因组的翻译和复制,结果将为相关的人类致病病毒提供一个模型。对这一基本机制的进一步了解将为新的治疗靶点和减毒疫苗设计提供洞察力。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Andrew Tuplin其他文献
Andrew Tuplin的其他文献
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{{ truncateString('Andrew Tuplin', 18)}}的其他基金
Mechanistic analysis of RNA-replication elements involved in early stages of chikungunya virus replication.
参与基孔肯雅病毒复制早期阶段的 RNA 复制元件的机制分析。
- 批准号:
MR/N01054X/1 - 财政年份:2016
- 资助金额:
$ 102.78万 - 项目类别:
Research Grant
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