How does Musashi 1 enhance Zika virus replication?

由昆虫传播的病毒导致了一些最重要的新出现的人类疾病。随着昆虫寄主范围的扩大，越来越多的种群正面临感染的风险。2015/2016年，寨卡病毒在中美洲和南美洲爆发，通过蚊子传播，伴随着新生儿小头症病例的增加。小头畸形是一种头围比平时小的情况，通常与发育缺陷有关。自那以后，寨卡病毒感染与神经细胞和大脑发育缺陷之间的因果联系已经牢固地建立起来，神经干细胞特别容易受到病毒的感染和破坏。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在接触寨卡病毒后都有患上衰弱疾病的风险。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。病毒基因组由一段名为RNA的核酸组成，它被复制并包装成新的病毒颗粒，然后释放出来传播感染。病毒复制可以受到感染细胞中存在的蛋白质的积极和消极影响。其中许多是与RNA结合的蛋白质，直接与病毒基因组相互作用。我们最近证明了一种名为Musashi-1的宿主蛋白强烈增强寨卡病毒的复制。已知武藏-1通过直接与其相应的RNA结合来影响特定蛋白质的表达。在对寨卡病毒感染高度敏感的神经前体细胞中存在高水平的武藏-1。武藏-1的一个突变，影响其与RNA的相互作用能力，也与先天性小头畸形有关，与寨卡病毒感染无关。综上所述，我们之前的发现支持了这样的假设，即寨卡病毒感染细胞中武藏-1的存在可能有助于在受影响的个体中观察到神经破坏和相关的脑发育缺陷。在这个项目中，我们将使用尖端技术来研究武藏-1和寨卡病毒之间的相互作用。我们将主要关注三个问题：1)武藏-1在寨卡病毒复制周期的哪个阶段发挥作用，以及武藏-1结合位点的突变是否会影响其在神经细胞中的复制能力？2)武藏-1通过与寨卡病毒RNA结合而被隔离是否破坏了武藏-1在神经细胞发育中的正常功能？3)武藏-1是否促进了寨卡病毒在小脑神经干细胞中的复制能力？通过这项工作，我们希望进一步了解一种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是如何增强寨卡病毒复制的，最终可能有助于我们开发更安全的疫苗，降低破坏性副作用的风险。

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.