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Inhibition of viral entry by interferon-induced proteins

干扰素诱导蛋白抑制病毒进入

基本信息

批准号：
10418696
负责人：
Gregory B Melikian
金额：
$ 35.6万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418696
关键词：
Acute Affect Animal Model Antiviral Response Binding Proteins Biological Assay Biophysics Biosensor Cell Culture Techniques Cell membrane Cells Cellular biology Chemicals Chimera organism Competence Data Dengue Dimerization Ebola Electrons Endosomes Exhibits Future IFITM1 gene Image Imaging Device Imaging Techniques Infection Infection prevention Influenza Influenza A virus Integral Membrane Protein Integration Host Factors Interferons Label Laboratories Lassa virus Link Lipids Measures Mechanics Mediating Membrane Microscopy Modeling Modulus Murine leukemia virus Pathway interactions Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Positioning Attribute Property Protein Family Proteins Publishing Reporting Resistance Resolution Role SARS coronavirus Severe Acute Respiratory Syndrome Site Technical Expertise Testing Time Transmembrane Transport VAPA gene Vesicle Viral Virus Visualization West Nile virus endosome membrane experimental study fluidity human pathogen in vivo innovation insight late endosome light microscopy lipid metabolism mechanical properties member novel novel virus particle protein distribution protein expression protein transport recruit trafficking virology virus envelope

项目摘要

Interferon-inducible transmembrane proteins (IFITMs) exhibit broad antiviral activity, both in cell culture and in vivo. IFITM expression has been shown to prevent infection of important human pathogens, including influenza, Ebola, West Nile and SARS viruses, by blocking viral fusion with target cells. The existence of IFITM-resistant viruses, such as Murine Leukemia and Lassa viruses, suggests that restriction occurs in a cellular compartment- specific manner. The mechanism by which fusion of diverse viruses is inhibited by IFITMs and the escape mechanisms from IFITM restriction are not understood, due in part to difficulties associated with visualization of their dynamic distribution in living cells. We made and validated functional fluorescently-tagged IFITM proteins and imaged, for the first time, single virus/IFITM co-trafficking and fusion. Pilot experiments suggest that viruses that co-traffic with IFITMs are trapped at a hemifusion stage, unable to form a fusion pore, whereas resistant viruses appear to be transported through endosomes devoid of IFITMs. We also discovered a novel role for phosphoinositides in viral fusion and the IFITM restriction phenotype. Our working hypothesis is that IFITMs block virus entry by: (i) trapping viral fusion at a dead-end hemifusion stage through by altering the properties of cell membranes; and (ii) favoring non-productive fusion with intralumenal vesicles within enlarged multivesicular compartments. We will test the working hypothesis using a panel of validated IFITM-sensitive and –resistant pseudoviruses and a powerful combination of virology, cell biology, membranebiophysics and advanced imaging techniques. Specifically, we will: (1) elucidate whether dynamic colocalization of IFITMs with viruses is a prerequisite for restriction; (2) determine whether IFITMs inhibit viral fusion by altering the mechanical properties of cell membranes that disfavor the transition from hemifusion to full fusion and/or through diverting the virus entry to a non-productive pathway; and (3) delineate the role of phosphoinositides in the IFITM restriction phenotype. Insights into the mechanism of IFITM-mediated virus restriction will provide important clues on how cells mount efficient antiviral responses and suggest new strategies for preventing infection.

干扰素诱导跨膜蛋白（IFITMs）在细胞培养和体外培养中均表现出广泛的抗病毒活性