How does Musashi 1 enhance Zika virus replication?
Musashi 1 如何增强寨卡病毒复制?
基本信息
- 批准号:BB/V000292/1
- 负责人:
- 金额:$ 102.13万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2021
- 资助国家:英国
- 起止时间:2021 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Viruses spread by insects cause some of the most important emerging human diseases. As the range of their insect hosts expands, increasing populations are becoming at risk to infection. An outbreak of Zika virus, spread by mosquitos, in Central and South America in 2015/2016 was accompanied by an increase in microcephaly cases in new-born babies. Microcephaly is a condition where the head circumference is smaller than usual and is typically associated with developmental defects. A causal link between Zika virus infection and defects in neural cell and brain development has since been firmly established with neural stem cells being particularly susceptible to infection, and destruction, by the virus. Recent evidence has also demonstrated a link between Zika virus infection and long-term cognitive dysfunction, suggesting that both adults and foetuses are at risk of debilitating disease following exposure. Like other viruses, Zika virus can only replicate once it enters a host cell. The virus genome consists of a single piece of nucleic acid called RNA that is replicated and packaged into new virus particles before being released to spread the infection. Virus replication can be positively and negatively affected by proteins present in the infected cell. Many of these are RNA-binding proteins that interact directly with the viral genome. We recently demonstrated that a host protein called Musashi-1 strongly enhances Zika virus replication. Musashi-1 is known to affect the expression of specific proteins by binding directly to their corresponding RNAs. High levels of Musashi-1 are present in the neural precursor cells that are highly susceptible to Zika virus infection. A mutation in Musashi-1 that affects its ability to interact with RNA is also linked to congenital microcephaly, independent of Zika virus infection. Together, our previous findings support the hypothesis that the presence of Musashi-1 in Zika virus infected cells may contribute to the neural destruction and associated brain development defects observed in affected individuals.In this project we will examine the interplay between Musashi-1 and Zika virus using cutting-edge techniques. We will focus on three main questions:1) At what stage of the Zika virus replication cycle does Musashi-1 exert its effect and can mutation of Musashi-1 binding sites in the Zika virus RNA affect its ability to reproduce in neuronal cells?2) Does sequestration of Musashi-1 through binding to the Zika virus RNA disrupt the normal function of Musashi-1 in neuronal cell development?3) Does Musashi-1 promote the ability of Zika virus to replicate in neural stem cells in mini brains? From this work we expect to advance our knowledge of how the presence of a protein that normally promotes neural cell development can make cells more permissive for Zika virus replication. This research can also reveal novel aspects of basic neurodevelopmental processes. Understanding how Musashi-1 enhances Zika virus replication may ultimately help us to develop safer vaccines with reduced risk of damaging side effects.
由昆虫传播的病毒引起一些最重要的新出现的人类疾病。随着昆虫宿主范围的扩大,越来越多的种群面临感染的风险。2015/2016年,中美洲和南美洲爆发了由蚊子传播的寨卡病毒,伴随着新生儿小头畸形病例的增加。小头畸形是一种头围比平常小的情况,通常与发育缺陷有关。寨卡病毒感染与神经细胞和大脑发育缺陷之间的因果关系已经牢固确立,神经干细胞特别容易受到病毒的感染和破坏。最近的证据也表明寨卡病毒感染与长期认知功能障碍之间存在联系,表明成人和胎儿在暴露后都有患上衰弱性疾病的风险。与其他病毒一样,寨卡病毒只有在进入宿主细胞后才能复制。病毒基因组由一段称为RNA的核酸组成,在释放以传播感染之前,RNA被复制并包装成新的病毒颗粒。病毒复制可以受到感染细胞中存在的蛋白质的正面和负面影响。其中许多是直接与病毒基因组相互作用的RNA结合蛋白。我们最近证明了一种名为Musashi-1的宿主蛋白质强烈增强了寨卡病毒的复制。已知Musashi-1通过直接结合其相应的RNA来影响特定蛋白质的表达。高水平的Musashi-1存在于对寨卡病毒感染高度敏感的神经前体细胞中。Musashi-1中影响其与RNA相互作用能力的突变也与先天性小头畸形有关,与寨卡病毒感染无关。综上所述,我们之前的研究结果支持了这样一个假设,即寨卡病毒感染细胞中存在的Musashi-1可能导致了在受影响个体中观察到的神经破坏和相关的大脑发育缺陷。在本项目中,我们将使用尖端技术研究Musashi-1和寨卡病毒之间的相互作用。我们将重点关注三个主要问题:1)Musashi-1在寨卡病毒复制周期的哪个阶段发挥作用,寨卡病毒RNA中Musashi-1结合位点的突变是否会影响其在神经元细胞中复制的能力?2)通过与寨卡病毒RNA结合来隔离Musashi-1是否会破坏Musashi-1在神经元细胞发育中的正常功能?3)Musashi-1是否促进寨卡病毒在迷你大脑神经干细胞中复制的能力?从这项工作中,我们希望推进我们的知识,即通常促进神经细胞发育的蛋白质的存在如何使细胞更容易复制寨卡病毒。这项研究还可以揭示基本神经发育过程的新方面。了解Musashi-1如何增强寨卡病毒复制可能最终有助于我们开发更安全的疫苗,降低破坏性副作用的风险。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells.
骨髓细胞干扰素分泌限制了正在发育和恶性的人类神经祖细胞的寨卡黄病毒感染。
- DOI:10.17863/cam.88340
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Bulstrode H
- 通讯作者:Bulstrode H
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Trevor Sweeney其他文献
Trevor Sweeney的其他文献
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{{ truncateString('Trevor Sweeney', 18)}}的其他基金
How does Musashi 1 enhance Zika virus replication?
Musashi 1 如何增强寨卡病毒复制?
- 批准号:
BB/V000292/2 - 财政年份:2021
- 资助金额:
$ 102.13万 - 项目类别:
Research Grant
The battle for the 5'end: dissecting a novel virus-specific translation mechanism driven by eIF3
5端之战:剖析由eIF3驱动的新型病毒特异性翻译机制
- 批准号:
BB/S007350/2 - 财政年份:2021
- 资助金额:
$ 102.13万 - 项目类别:
Research Grant
The battle for the 5'end: dissecting a novel virus-specific translation mechanism driven by eIF3
5端之战:剖析由eIF3驱动的新型病毒特异性翻译机制
- 批准号:
BB/S007350/1 - 财政年份:2019
- 资助金额:
$ 102.13万 - 项目类别:
Research Grant
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