Restriction of Viral Membrane Fusion and Entry by IFITM Proteins

IFITM 蛋白对病毒膜融合和进入的限制

• 批准号: 8896142
• 负责人: Shan-Lu Liu
• 金额: $ 39.3万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-04 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896142
• 关键词: Adopted; Affect; Amino Acids; Antiviral Agents; Antiviral Therapy; Applications Grants; Biochemical; Biological Models; Biophysical Process; Cell fusion; Cell membrane; Cells; Cellular biology; Cholesterol; Consensus; Development; Ebola virus; Event; Fluorescence; Fluorescent Dyes; Goals; Growth; HIV-1; Health; Human; IFITM1 gene; Image; Imaging Techniques; Immunity; Infection; Influenza A virus; Integral Membrane Protein; Interferons; Knowledge; Label; Lead; Lipids; Measures; Mechanics; Mediating; Membrane; Membrane Fluidity; Membrane Fusion; Microscopy; Molecular; Molecular Biology; Orthologous Gene; Peptides; Post-Translational Protein Processing; Process; Property; Reporting; Research; Retroviridae; Role; SARS coronavirus; Semliki forest virus; Severe Acute Respiratory Syndrome; Staging; Testing; Therapeutic Agents; Therapeutic Intervention; Tyrosine Phosphorylation; Ubiquitination; Viral; Viral Fusion Proteins; Virus; Virus Diseases; Work; base; design; inhibitor/antagonist; novel; novel strategies; novel therapeutics; research study; vesicular stomatitis virus G protein

DESCRIPTION (provided by applicant): The long-term objective of our research is to better understand the mechanisms of viral entry and the possible implications for therapeutic interventions. To achieve these goals, we have recently studied the interferon-inducible transmembrane (IFITM) proteins that potently inhibit entry and infection of a wide range of viruses, including those of the highly pathogenic influenza A virus (IAV), SARS coronavirus, Ebolavirus (EBOV), and HIV-1. We showed that IFITM proteins profoundly inhibit cell-cell fusion induced by IAV HA, Semliki Forest virus (SFV) E1, and vesicular stomatitis virus (VSV) G proteins, which represent class I, II and III viral fusion proteins, respectively. Further experiments revealed that IFITMs block the creation of viral membrane hemifusion, which is consistent with their ability to decrease membrane fluidity. Interestingly, we observed that some viruses are more sensitive than others to inhibition by particular types of IFITMs, suggesting that IFITM-mediated restriction of viral entry can, in addition to broad inhibitions, be virus dependent The specific aims of this project are (1) to determine the molecular and biophysical mechanisms by which IFITMs inhibit viral membrane fusion, (2) to understand the molecular basis by which IFITM proteins change lipid properties and membrane mechanics, thereby inhibiting viral membrane fusion, and (3) to elucidate the molecular and cellular control mechanisms that govern the differential antiviral activities of IFITMs. Collectively, understanding the underlying mechanisms of IFITMs as proposed in this work will significantly advance our knowledge of IFN-mediated intrinsic immunity against viral entry. Results from the proposed experiments will aid the development of novel therapeutic agents against viral infections.

描述（由申请人提供）：我们研究的长期目标是更好地了解病毒进入的机制以及对治疗干预措施的可能影响。为了实现这些目标，我们最近研究了干扰素诱导跨膜 (IFITM) 蛋白，该蛋白可有效抑制多种病毒的进入和感染，包括高致病性甲型流感病毒 (IAV)、SARS 冠状病毒、埃博拉病毒 (EBOV) 和 HIV-1。我们发现，IFITM 蛋白可显着抑制 IAV HA、塞姆利基森林病毒 (SFV) E1 和水泡性口炎病毒 (VSV) G 蛋白（分别代表 I 类、II 类和 III 类病毒融合蛋白）诱导的细胞间融合。进一步的实验表明，IFITM 可以阻止病毒膜半融合的产生，这与它们降低膜流动性的能力是一致的。有趣的是，我们观察到某些病毒比其他病毒对特定类型的 IFITM 的抑制更敏感，这表明 IFITM 介导的病毒进入限制除了广泛的抑制之外，还可以是病毒依赖性的。该项目的具体目标是 (1) 确定 IFITM 抑制病毒膜融合的分子和生物物理机制，(2) 了解 IFITM 蛋白改变脂质特性和膜力学，从而抑制病毒膜融合的分子基础，(3) 阐明控制 IFITM 差异抗病毒活性的分子和细胞控制机制。总的来说，了解本工作中提出的 IFITM 的基本机制将显着增进我们对 IFN 介导的针对病毒进入的内在免疫的了解。拟议实验的结果将有助于开发针对病毒感染的新型治疗剂。