Interplay between flaviviruses and lipids

黄病毒是严重的全球卫生挑战。对这些病毒的研究，包括寨卡病毒(ZIKV)和登革热病毒(DENV)，对于帮助防止它们各自的流行病传播至关重要，理想情况下将导致获得治疗方法。更深入地了解病毒复制的机制将有助于抗病毒的开发。黄病毒生命周期中特别鲜为人知的一个阶段是宿主细胞进入的过程。对于许多黄病毒，包括ZIKV和DENV，进入似乎需要宿主细胞上存在磷脂酰丝氨酸(PS)受体。这一发现导致了这些受体与这些病毒膜被膜中的磷脂结合的模型，其方式与细胞膜蛋白与病毒糖蛋白的相互作用非常相似。这一过程被称为“凋亡拟态”，因为它类似于吞噬细胞利用PS受体识别表面显示PS的凋亡细胞的机制。如果这种宿主细胞进入模型是正确的，那么病毒颗粒结合足够浓度的与PS受体相互作用的脂类，包括PS和/或磷脂酰乙醇胺(PE)将是至关重要的。到目前为止，ZIKV和DENV的脂质体还没有定义。此外，如果这些颗粒的脂膜中需要PS和/或PS，其获取机制仍有待确定。由于黄病毒通过发芽进入内质网获得其包膜，可以想象这是通过随机抽样ER膜而发生的，众所周知，ER膜包括PS。然而，同样进入内质网的丙型肝炎病毒不会将PS结合到其颗粒中。因此，ZIKV要么刺激PS的产生和/或内质网浓度，要么在病毒粒子被膜期间主动选择PS。为了解决这个问题，我们建议进行实验，比较ZIKV和DENV颗粒与幼稚和感染的全细胞和ER膜的脂组成。该项目的结果将提供对黄病毒宿主细胞相互作用和复制机制的深入见解，这可能有助于开发ZIKV的治疗努力，并可能进一步应用于抗击未来的其他病毒爆发。

Flaviviruses represent serious global health challenges. Research on these viruses, including Zika virus (ZIKV) and Dengue virus (DENV), is crucial to help prevent the spread of their respective epidemics and will ideally result in the availability of therapies. Antiviral development would be aided by a deeper understanding of the mechanisms of viral replication. One stage of the flavivirus life cycle that is particularly poorly understood is the process of host cell entry. For many flaviviruses, including ZIKV and DENV, entry appears to require the presence of phosphatidylserine (PS) receptors on host cells. This finding has led to the model in which these receptors bind to the phospholipids in the membrane envelope of these viruses much in the same way that a cell membrane protein interacts with a viral glycoprotein. This process is termed `apoptotic mimicry', as it resembles the mechanism by which phagocytes use PS receptors to recognize apoptotic cells that display PS on their surface. If this model of host cell entry is correct, it would be critical for the viral particle to incorporate a sufficient concentration of lipids that interact with PS receptor, including PS and/or phosphatidylethanolamine (PE). To date, the lipidome of ZIKV and DENV has not been defined. Furthermore, if PS and/or is required in the lipid envelope of these particles, the mechanism of its acquisition remains to be determined. Since flaviviruses acquire their envelope by budding into the ER, it is conceivable that this occurs by random sampling of ER membranes, which are known to include PS. However, the hepatitis C virus, which also buds into the ER, does not incorporate PS into its particles. Thus, ZIKV either stimulates the production and/or ER concentration of PS, or it actively selects PS during virion envelopment. To address this question, we propose experiments to compare the lipid composition of ZIKV and DENV particles to those of naïve and infected whole cells and ER membranes. The results of this project will provide in-depth insights into flavivirus host cell interactions and replication mechanisms that may aid in the development of therapeutic efforts for ZIKV and could perhaps be further applied in combating other future virus outbreaks.