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：
Trevor Sweeney
金额：
$ 102.13万
依托单位：
University of Cambridge
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：
https://gtr.ukri.org/projects?ref=BB%2FV000292%2F1
关键词：
How does Musashi enhance Zika

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.

昆虫传播的病毒引起了一些最重要的新兴人类疾病。随着昆虫宿主的范围扩大，越来越多的人群正处于感染的风险。 2015/2016年，蚊子病毒爆发，由蚊子传播，伴随着新生婴儿的小头畸形病例的增加。小头畸形是头围比平常小，通常与发育缺陷相关的条件。此后，Zika病毒感染与神经细胞和脑发育缺陷之间的因果关系已牢固地确定，神经干细胞特别容易受到该病毒感染和破坏的影响。最近的证据还表明，寨卡病毒感染与长期认知功能障碍之间存在联系，这表明成年人和胎儿都有暴露后疾病使人衰弱的风险。像其他病毒一样，寨卡病毒只有进入宿主细胞后才能复制。病毒基因组由一块称为RNA的核酸组成，该核酸在释放以传播感染之前被复制并包装到新的病毒颗粒中。病毒复制可以受到感染细胞中存在的蛋白质的积极和负面影响。其中许多是与病毒基因组直接相互作用的RNA结合蛋白。我们最近证明，一种称为Musashi-1的宿主蛋白会强烈增强Zika病毒复制。已知Musashi-1通过直接与其相应的RNA结合来影响特定蛋白的表达。高水平的musashi-1存在于高度易受寨卡病毒感染的神经前体细胞中。 Musashi-1中影响其与RNA相互作用的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。总之，我们以前的发现支持以下假设：寨卡病毒感染细胞中穆萨什-1的存在可能有助于神经破坏和相关的脑发育缺陷。我们将重点关注三个主要问题：1）在寨卡病毒复制周期的哪个阶段，Musashi-1会发挥其作用，并且可以突变Zika病毒RNA中的Musashi-1结合位点会影响其在神经元细胞中繁殖的能力吗？寨卡病毒在迷你大脑中神经干细胞中复制的能力？从这项工作中，我们期望我们对通常促进神经细胞发育的蛋白质的存在如何使细胞更具允许的寨卡病毒复制的知识。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Zika病毒复制可能最终可能有助于我们开发具有降低副作用风险的更安全的疫苗。