Interplay between flaviviruses and lipids

黄病毒和脂质之间的相互作用

• 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
• 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

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.

黄病毒是严重的全球健康挑战。对这些病毒的研究，包括寨卡病毒（ZIKV）和登革热病毒（DENV），对于帮助预防各自流行病的传播至关重要，并将理想地导致治疗的可用性。对病毒复制机制的深入了解将有助于抗病毒药物的开发。黄病毒生命周期的一个阶段，特别是知之甚少的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。这一发现导致了这样的模型，其中这些受体与这些病毒的膜包膜中的磷脂结合，其方式与细胞膜蛋白与病毒糖蛋白相互作用的方式大致相同。这一过程被称为“凋亡模拟”，因为它类似于吞噬细胞使用PS受体识别在其表面上显示PS的凋亡细胞的机制。如果这种宿主细胞进入的模型是正确的，则病毒颗粒掺入足够浓度的与PS受体相互作用的脂质（包括PS和/或磷脂酰乙醇胺（PE））将是至关重要的。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，则其获取的机制仍有待确定。由于黄病毒通过出芽进入ER获得其包膜，因此可以想象这是通过随机取样ER膜发生的，已知ER膜包括PS。然而，也在ER中出芽的丙型肝炎病毒并不将PS掺入其颗粒中。因此，ZIKV刺激PS的产生和/或ER浓度，或者其在病毒体增殖期间主动选择PS。为了解决这个问题，我们提出了实验来比较ZIKV和DENV颗粒的脂质组成与幼稚和感染的全细胞和ER膜的脂质组成。该项目的结果将为黄病毒宿主细胞相互作用和复制机制提供深入的见解，这可能有助于ZIKV治疗工作的发展，并可能进一步应用于对抗其他未来的病毒爆发。