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.

黄病毒代表着严重的全球健康挑战。对这些病毒（包括寨卡病毒（ZIKV）和登革热病毒（DENV））的研究对于帮助防止各自流行病的传播至关重要，并且理想情况下将导致抗病毒疗法的开发。借助对病毒复制机制的更深入了解，我们对黄病毒生命周期的一个阶段了解得特别少，那就是对许多黄病毒（包括 ZIKV 和 DENV）的进入宿主细胞的过程。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包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相互作用的方式非常相似。这个过程被称为“凋亡拟态”，因为它类似于吞噬细胞使用 PS 受体识别在其表面展示 PS 的凋亡细胞的机制。如果是正确的，那么病毒颗粒掺入足够浓度的与 PS 受体相互作用的脂质至关重要，包括 PS 和/或磷脂酰乙醇胺 (PE)。迄今为止，如果 PS 尚未定义 ZIKV 和 DENV 的脂质组。和/或在这些颗粒的脂质包膜中是必需的，其获得的机制仍有待确定，因为黄病毒通过出芽进入内质网获得其包膜，可以想象这是通过随机采样发生的。已知含有 PS 的 ER 膜，然而，同样在 ER 中萌芽的丙型肝炎病毒不会将 PS 掺入其颗粒中，因此，ZIKV 要么刺激 PS 的产生和/或 ER 浓度，要么刺激 PS 的产生。为了解决这个问题，我们提出了将 ZIKV 和 DENV 颗粒的脂质成分与幼稚和感染的全细胞和 ER 膜的脂质成分进行比较的实验。将深入了解黄病毒宿主细胞相互作用和复制机制，这可能有助于开发 ZIKV 治疗方法，并可能进一步应用于对抗未来其他病毒的爆发。