Interplay between flaviviruses and lipids

黄病毒和脂质之间的相互作用

基本信息

批准号：
9750982
负责人：
Matthew J Evans
金额：
$ 26.13万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-05 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750982
关键词：
Address African Anabolism Antibodies Antiviral Agents Antiviral Therapy Apoptotic Asians Binding Blood Circulation Brazil Cell Communication Cell Membrane Proteins Cells Complex Mixtures Culicidae Dengue Virus Development Disease Outbreaks Endoplasmic Reticulum Epidemic Epitopes Family Flaviviridae Flavivirus Flavivirus Infections Foundations Future Glycoproteins Goals Hepatitis C virus Human Infection Life Cycle Stages Lipids Mass Spectrum Analysis Mediating Membrane Metabolic Pathway Modeling Molecular Virology Mutagenesis Phagocytes Phosphatidylethanolamine Phosphatidylserines Phospholipids Play Process Production Public Health Research Sampling Surface Therapeutic Intervention Time Viral Virion Virus Virus Replication West Nile virus Work Yellow fever virus Zika Virus combat env Gene Products experimental study global health human pathogen innovation insight mimicry mutant new therapeutic target pandemic disease particle phosphatidylserine receptor prevent receptor binding therapeutic development virus envelope

项目摘要

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.

黄病毒代表了严重的全球健康挑战。这些病毒的研究，包括寨卡病毒（ZIKV）和登革热病毒（DENV），对于帮助防止各自发作的传播至关重要，理想情况下将导致疗法的可用性。对病毒复制机制的更深入的理解将有助于抗病毒发育。尤其知之甚少的黄素生命周期的一个阶段是宿主细胞进入的过程。对于包括ZIKV和DENV在内的许多黄酮病毒，入口似乎需要在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包膜中磷脂结合的模型，就像细胞膜蛋白与病毒糖蛋白相互作用一样。该过程称为“凋亡模仿”，因为它类似于吞噬细胞使用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，那么对于病毒颗粒来说，将足够的脂质浓度与PS接收器相互作用，包括PS和/或磷脂酰乙醇胺（PE）至关重要。迄今为止，尚未定义ZIKV和DENV的脂质组。此外，如果在这些颗粒的脂质包膜中需要PS和/或或/或或/或或/或，则其采集机制仍有待确定。由于黄病毒是通过萌芽到ER来获取其包膜的，因此可以想象，这是通过随机采样ER膜发生的，ER膜包括PS。然而，也芽到ER的丙型肝炎病毒不会将PS纳入其颗粒中。这是ZIKV刺激PS的产生和/或ER浓度，或者在病毒座包膜中积极选择PS。为了解决这个问题，我们提出了实验，以将ZIKV和DENV颗粒的脂质组成与幼稚和感染的全细胞和ER机制的脂质组成进行比较。该项目的结果将提供对Flavivirus宿主细胞相互作用和复制机制的深入见解，这些机制可能有助于开发ZIKV的热努力，并可能进一步应用于对抗其他未来病毒暴发。