Mechanism of Interaction between Influenza Hemagglutinin and Host Cell Phosphoinositides

流感血凝素与宿主细胞磷酸肌醇相互作用的机制

• 批准号: 10045796
• 负责人: SAMUEL T HESS
• 金额: $ 42.82万
• 依托单位: UNIVERSITY OF MAINE ORONO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045796
• 关键词: Actin-Binding Protein; Actins; Acylation; Address; Affect; Amino Acids; Antiviral Agents; Antiviral Therapy; Binding; Cell membrane; Cells; Cellular Structures; Charge; Cytoplasmic Tail; Cytoskeleton; Data; Databases; Diffuse; Diffusion; Drug Targeting; Drug usage; Ebola; Energy Transfer; Fluorescence; Fluorescence Spectroscopy; HIV; Hemagglutinin; Image; Infection; Influenza; Influenza Hemagglutinin; Lead; Length; Life Cycle Stages; Lipids; Mediating; Membrane; Membrane Fusion; Membrane Glycoproteins; Methods; Microscopy; Modeling; Mutate; Mutation; Pattern; Pharmaceutical Preparations; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Property; Proteins; Publishing; Regulation; Resistance; Resolution; Respiratory System; Seasons; Signal Pathway; Site; Spectrum Analysis; Structure; Surface; Testing; Time; Transmembrane Domain; Update; Vaccines; Viral; Viral Proteins; Virus; acyl group; cofilin; density; influenzavirus; mortality; mutant; spatial relationship; spectroscopic imaging

Influenza virus causes significant illness and mortality in the U.S. and worldwide. Vaccines offer some protection, but must be continuously tailored to seasonal mutations of the virus. Some strains of influenza are resistant to one or more of the limited number of available anti-viral drugs. New strategies which attack invariant features of the virus are desperately needed. The protein hemagglutinin, found on the surface of the virus, allows the virus to bind to host cells and enter. Entry depends on high density clusters of hemagglutinin within the viral membrane, but the mechanism of cluster formation is unknown. This project will address the fundamental question of how hemagglutinin forms clusters, even in the absence of other viral components, by hijacking cellular components. We recently discovered that hemagglutinin interacts with a particular host cell lipid (PIP2) that is able to control the host cell cytoskeleton and several signaling pathways that have been implicated previously in infection. This project will investigate the mechanism of interaction between hemagglutinin and PIP2 using super- resolution microscopy and other fluorescence methods, targeting the portions of hemagglutinin that are invariant and therefore less likely to mutate over time. Results will help identify new targets for anti-viral drugs and illuminate how influenza is able to modify the host cell cytoskeleton and plasma membrane for its own life cycle.

流感病毒在美国和全世界引起严重的疾病和死亡。疫苗提供 一些保护，但必须不断调整，以适应季节性突变的病毒。一些 流感病毒株对有限数量的可用抗病毒药物中的一种或多种具有抗性 毒品迫切需要攻击病毒不变特征的新策略。的 在病毒表面发现的一种蛋白质血凝素，使病毒能够与宿主细胞结合 然后进去进入依赖于病毒膜内高密度的血凝素簇， 但团簇形成的机理尚不清楚。该项目将解决基本的 血凝素如何形成簇的问题，即使在没有其他病毒成分的情况下， 通过劫持手机组件我们最近发现血凝素与一种 能够控制宿主细胞细胞骨架的特定宿主细胞脂质（PIP2）和几种 之前与感染有关的信号通路。该项目将 用超声波技术研究血凝素与PIP2相互作用的机制。 分辨率显微镜和其他荧光方法，靶向部分血凝素 它们是不变的，因此不太可能随时间发生突变。结果将有助于确定新的 靶点的抗病毒药物，并阐明如何流感能够修改宿主细胞 细胞骨架和细胞膜组成其生命周期。