Spatiotemporal Regulation of Membrane Raft Trafficking in Virus Activated Cells
病毒激活细胞膜筏运输的时空调控
基本信息
- 批准号:8204961
- 负责人:
- 金额:$ 7.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-12-15 至 2012-11-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAcuteAdhesionsAffinityAmericanBerylliumBindingBiochemicalBiological AssayBiological ModelsCD55 AntigensCardiopulmonaryCell surfaceCellsCellular biologyClathrinCollaborationsDevelopmentDiseaseDissectionDoseEndocytosisEventFDA approvedFluorescent ProbesFocal AdhesionsGPI Membrane AnchorsGlycoproteinsHantavirusHemorrhagic Fever with Renal SyndromeInfectionIntegrinsLabelLaboratoriesLeadLifeLinkLipidsMeasurementMediatingMediationMembraneMembrane MicrodomainsMethodsMicroscopyMolecularMonitorMovementOrganellesPathogenesisPathway interactionsPatternPharmaceutical PreparationsPositioning AttributeProteinsReagentRecruitment ActivityRegulationResearchRodentRouteScienceSignal TransductionSin Nombre virusSiteSyndromeSystemTechnologyTestingTimeTitrationsTranslatingUltraviolet RaysVaccinesViralVirionVirusVirus DiseasesVirus ReceptorsWorkbasebiosafety level 2 facilitycrosslinkexperiencehigh throughput screeninghuman diseaseinhibitor/antagonistinnovationkillingsnovel strategiesobligate intracellular parasiteparticlepolarized cellpositional cloningpreventprogramspublic health relevancereceptorresearch studysmall moleculespatiotemporaltooltraffickinguptakeviral RNAvirology
项目摘要
DESCRIPTION (provided by applicant): Hantaviruses can cause two often-severe diseases of humans: hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome (HCPS). The lack of vaccines or specific drugs to prevent or treat HCPS disease, and the requirement for conducting experiments in a biosafety level 3 laboratory (BSL-3), have limited the ability to effectively probe the mechanism of infection and disease pathogenesis. We have therefore initiated a program to study Sin Nombre virus (SNV) killed with a calibrated dose of UV radiation as a model system to dissect its mechanism of cellular entry in BSL-2 facilities. As obligate intracellular parasites, hantaviruses depend on cellular mechanisms for entry and release from their host cells. Membrane rafts on the cell surface are often the originating point of cell signaling, adhesion and endocytosis. Viruses use signaling elements that are bundled in membrane rafts and co-opt the cellular endocytic machinery to achieve entry and productive infection. However, mechanistic dissection of virus entry has been hampered because glycoproteins of many hantaviruses are difficult to express and no tractable reverse genetics system is available. Therefore, new approaches to understanding the mechanistic steps of infection are needed and critical to the identification of targets for blocking infection. We demonstrated that UV-killed SNV attaches to the glycosylphosphatidylinositol (GPI)-anchored protein decay accelerating factor (DAF/CD55) and low affinity state ???3 integrins in a manner that parallels the results obtained from infectivity assays using live virions. Therefore, we were able to monitor virus uptake in real time and show that the initial binding of SNV to DAF is followed by Rac1 stimulated actin remodeling, disassembly of focal adhesions, and leads to loss of cell-cell contact and cell-substrate adhesion. Our observations are significant because they offer the first temporal and spatial dissection of the events involved in hantavirus entry and offer a plausible mechanistic explanation for the acute cardiopulmonary syndrome caused by virus infection. To test this hypothesis we will pursue the following aims. Aim 1: To define the spatiotemporal redistribution of cognate receptors (DAF/CD55 and ???3 integrins) following hantavirus binding. Aim 2: To define the mechanism of hantavirus endocytosis and its relationship to ???3 and DAF.
PUBLIC HEALTH RELEVANCE: Hantavirus cardiopulmonary syndrome is a progressive and often fatal form of human disease caused by Sin Nombre Virus (SNV), which is a rodent virus endemic to the American Southwest. This proposal brings together a unique team employing tools and concepts of biophysical science, molecular cell biology and virology to study the mechanism used by hantaviruses to enter cells. We are able to use state of the art tools to examine how viruses hijack the cellular machinery of endocytosis to enter and infect cells through the mediation of specialized membrane microdomains called lipid rafts. The long-term result of this work could be used to determine route of entry for anti-viral treatment.
描述(由申请人提供):汉坦病毒可能引起两种经常性的人类疾病:肾脏综合征的出血热或汉塔病毒心肺综合征(HCPS)。缺乏预防或治疗HCP疾病的疫苗或特定药物,以及在生物安全3级实验室(BSL-3)中进行实验的要求限制了有效探测感染和疾病发病机理的能力。因此,我们已经启动了一项计划,研究了用校准剂量的紫外线辐射杀死的罪恶nombre病毒(SNV),作为模型系统,以剖定其在BSL-2设施中的细胞进入机制。作为强制性细胞内寄生虫,汉坦病毒取决于细胞机制的进入和从其宿主细胞中释放。细胞表面上的膜筏通常是细胞信号传导,粘附和内吞作用的起源点。病毒使用捆绑在膜筏中的信号传导元件并选择细胞内吞机器来实现进入和生产性感染。然而,由于许多汉坦病毒的糖蛋白很难表达,并且没有可拖动的反向遗传学系统,因此病毒进入的机理解剖受到了阻碍。因此,需要新的方法来理解感染的机理步骤,并且对于鉴定阻断感染的靶标的识别至关重要。我们证明了UV-killed SNV附着在糖基磷脂酰肌醇(GPI)锚定的蛋白质衰减加速因子(DAF/CD55)和低亲和力状态?3整合蛋白上,以一种与使用活体病毒体从感染性分析获得的结果的方式。因此,我们能够实时监测病毒摄取,并表明SNV与DAF的初始结合随后是Rac1刺激的肌动蛋白重塑,局灶性粘附的拆卸,并导致细胞 - 细胞接触和细胞覆盖粘附的丧失。我们的观察结果很大,因为它们提供了对汉塔病毒进入的事件的第一个时间和空间解剖,并为病毒感染引起的急性心肺综合征提供了合理的机械解释。为了检验这一假设,我们将追求以下目标。目标1:定义汉坦病毒结合后的同源受体(DAF/CD55和??? 3整合素)的时空重新分布。目标2:定义汉塔病毒内吞作用的机理及其与“?3和DAF”的关系。
公共卫生相关性:汉塔病毒心肺综合征是由罪恶诺姆布雷病毒(SNV)引起的一种进步性且通常是致命的人类疾病的形式,这是美国西南部特有的啮齿动物病毒。该提案汇集了一个独特的团队,采用生物物理科学,分子细胞生物学和病毒学的工具和概念来研究汉坦病毒进入细胞的机制。我们能够使用最先进的工具来检查病毒如何劫持内吞作用的细胞机制,通过介导称为脂质筏的专用膜微区域的介导,进入和感染细胞。这项工作的长期结果可用于确定抗病毒治疗的进入途径。
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)
Small-Volume Flow Cytometry-Based Multiplex Analysis of the Activity of Small GTPases.
- DOI:10.1007/978-1-4939-8612-5_13
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Simons P;Bondu V;Wandinger-Ness A;Buranda T
- 通讯作者:Buranda T
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