Membrane Rearrangements in Flavivirus Infected Cells

黄病毒感染细胞的膜重排

基本信息

  • 批准号:
    7876900
  • 负责人:
  • 金额:
    $ 19.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-19 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A hallmark of infection with positive strand RNA viruses is the impressive intracellular membrane rearrangements induced within host cells to facilitate replication of their viral genomes. This project will use a multidisciplinary approach to investigate the molecular mechanisms that drive intracellular membrane rearrangements during flavivirus infection. The focus of this project will be on dengue virus, an NIAID category A priority pathogen, because of its medical importance and the substantial data and reagents we and others have accumulated over the last several years. Dengue virus causes about 50-100 million infections per year making it the most important arbovirus worldwide. It belongs to the flavivirus genus, which comprises more than 70 members, many of which are important human pathogens. Infection of cells with dengue virus results in enhanced synthesis of new lipid-derived structures and extensive membrane rearrangements. It has been shown that these membranous structures are required for a productive dengue virus infection, however, the molecular requirements that underlie the formation of these structures remains largely unknown. This project will determine the membrane composition of these structures and the cellular signaling cascades and trafficking pathways recruited by dengue virus for their formation and function. A high-resolution mass spectrometry based approach has been developed to initially identify the lipid-mediators important for the formation of these intracellular membranous structures. Preliminary data from these analyses have indicated a clear difference between the overall lipid composition of dengue virus infected cells compared to uninfected cells. These observations will be extended to determine how these changes in lipid profiles translate to the observed ultrastructural modifications in dengue virus infected cells. High-resolution mass spectrometry analyses will be employed to identify the differentially expressed lipids. Specifically isolated membrane fractions will be analyzed from infected cells and used to determine the temporal changes in lipid profile and their accumulation in these structures during the course of infection. Using lifetime imaging technology and confocal microscopy, the temporal redistribution of key lipids into these membranous structures will be visualized and these will be correlated with the various stages of the viral life cycle including viral gene expression, viral RNA replication and virus assembly. Using molecular genetics we will define the viral gene products responsible for these rearrangements. Ultimately, the experiments proposed should provide a framework for understanding the virus-induced alterations in lipid metabolism and ultrastructure in dengue virus infected cells and provide the basis for future experiments detailing the lipid-mediated molecular interactions between virus and host. PUBLIC HEALTH RELEVANCE: The flaviviruses represent a large and significant set of viral pathogens that infect hundreds of millions of people each year. By discovering how dengue virus changes the lipid components of cells, it may be possible to better understand how the virus causes disease, and may give insight into how to design novel therapeutics that modify these changes to inhibit the virus.
描述(由申请人提供):阳性链RNA病毒感染的标志是宿主细胞内诱导的令人印象深刻的细胞内膜重排,以促进其病毒基因组的复制。该项目将使用多学科方法来研究在黄病毒感染期间驱动细胞内膜重排的分子机制。该项目的重点将放在登革热病毒上,这是NIAID类别的优先病原体,由于其医学重要性以及我们和其他人在过去几年中积累的大量数据和试剂。登革热病毒每年会引起约500-1亿次感染,使其成为全球最重要的Arbovirus。它属于黄病毒属,其中包括70多个成员,其中许多是重要的人类病原体。用登革热病毒感染细胞会增强新脂质衍生结构和广泛的膜重排的合成。已经表明,这些膜结构是生产性登革热病毒感染所必需的,但是,这些结构形成的基础的分子需求在很大程度上是未知的。该项目将确定这些结构的膜组成以及登革热病毒招募的细胞信号传导级联和运输途径的形成和功能。已经开发了一种基于高分辨率的质谱方法,以最初确定对这些细胞内膜结构的形成重要的脂质介体。这些分析的初步数据表明,与未感染的细胞相比,登革热病毒感染细胞的总脂质组成之间存在明显差异。这些观察结果将扩展,以确定脂质谱的这些变化如何转化为登革热病毒感染细胞中观察到的超微结构修饰。将采用高分辨率质谱分析来识别差异表达的脂质。将从感染细胞中分析特定分离的膜级分,并用于确定脂质谱的时间变化及其在感染过程中它们在这些结构中的积累。使用寿命成像技术和共聚焦显微镜,将对这些膜结构的关键脂质的时间重新分布可视化,这些脂质将与病毒生命周期的各个阶段相关,包括病毒基因表达,病毒RNA复制和病毒组装。使用分子遗传学,我们将定义负责这些重排的病毒基因产物。最终,提出的实验应提供一个框架,以理解登革热病毒感染细胞中脂质代谢和超微结构的变化,并为未来的实验提供详细介绍脂质介导的分子相互作用的基础。 公共卫生相关性:黄病毒代表着一组大量大量的病毒病原体,每年感染数亿人。通过发现登革热病毒如何改变细胞的脂质成分,有可能更好地理解病毒如何引起疾病,并可以深入了解如何设计新的治疗剂以修饰这些变化以抑制病毒。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Dengue virus infection perturbs lipid homeostasis in infected mosquito cells.
  • DOI:
    10.1371/journal.ppat.1002584
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Perera R;Riley C;Isaac G;Hopf-Jannasch AS;Moore RJ;Weitz KW;Pasa-Tolic L;Metz TO;Adamec J;Kuhn RJ
  • 通讯作者:
    Kuhn RJ
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Richard J. Kuhn其他文献

Identification and biology of cellular receptors for the coxsackie B viruses group.
柯萨奇 B 病毒组细胞受体的鉴定和生物学。

Richard J. Kuhn的其他文献

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{{ truncateString('Richard J. Kuhn', 18)}}的其他基金

Structural analysis of HCV E1E2 glycoproteins
HCV E1E2 糖蛋白的结构分析
  • 批准号:
    10797243
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
Structural analysis of HCV E1E2 glycoproteins
HCV E1E2 糖蛋白的结构分析
  • 批准号:
    10205552
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
Structural analysis of HCV E1E2 glycoproteins
HCV E1E2 糖蛋白的结构分析
  • 批准号:
    10409764
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
Rapid Generation of Vaccine Candidates Against Novel Coronavirus (SARS-CoV-2) Using the Bacteriophage T4 Nanoparticle Platform
使用噬菌体 T4 纳米颗粒平台快速生成针对新型冠状病毒 (SARS-CoV-2) 的候选疫苗
  • 批准号:
    10265803
  • 财政年份:
    2020
  • 资助金额:
    $ 19.06万
  • 项目类别:
Molecular Functions of NS1 Virulence Protein from Dengue and Zika Viruses
登革热和寨卡病毒 NS1 毒力蛋白的分子功能
  • 批准号:
    9542638
  • 财政年份:
    2017
  • 资助金额:
    $ 19.06万
  • 项目类别:
Structural Studies of Togaviruses
披膜病毒的结构研究
  • 批准号:
    10091384
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
Structural Studies of Togaviruses
披膜病毒的结构研究
  • 批准号:
    10555263
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
Structural Studies of Togaviruses
披膜病毒的结构研究
  • 批准号:
    10331737
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
A MultiDisciplinary Cancer Research Facility at Purdue University
普渡大学的多学科癌症研究机构
  • 批准号:
    7877492
  • 财政年份:
    2010
  • 资助金额:
    $ 19.06万
  • 项目类别:
Inhibition of flavivirus replication and assembly
抑制黄病毒复制和组装
  • 批准号:
    7672018
  • 财政年份:
    2009
  • 资助金额:
    $ 19.06万
  • 项目类别:

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探索基孔肯雅病毒及其伊蚊媒介的共同进化潜力
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