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

基本信息

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
项目类别：
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

项目摘要

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造成严重疾病和死亡。疫苗优惠一些保护，但必须不断针对病毒的季节性突变进行调整。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药性药物。迫切需要攻击病毒不变特征的新策略。这病毒表面发现的蛋白质血凝素使病毒能够与宿主细胞结合并输入。进入取决于病毒膜内高密度的血凝素簇，但簇形成的机制尚不清楚。该项目将解决基本问题即使没有其他病毒成分，血凝素如何形成簇的问题，通过劫持细胞成分。我们最近发现血凝素与特定的宿主细胞脂质（PIP2）能够控制宿主细胞的细胞骨架和一些先前与感染有关的信号通路。该项目将使用超级研究研究血凝素和 PIP2 之间的相互作用机制分辨率显微镜和其他荧光方法，针对血凝素部分它们是不变的，因此不太可能随着时间的推移而发生突变。结果将有助于识别新的抗病毒药物的靶标并阐明流感如何改变宿主细胞细胞骨架和质膜有其自身的生命周期。