Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

病毒进入细胞的机制和限制进入的抗病毒屏障

• 批准号: 10486971
• 负责人: Alex Compton
• 金额: $ 44.51万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486971
• 关键词: Address; Affect; Amino Acids; Antiviral Agents; Antiviral Therapy; CD4 Positive T Lymphocytes; Categories; Cell fusion; Cell-Matrix Junction; Cells; Co-Immunoprecipitations; Consequentialism; Cytoplasm; Development; Evolution; Fluorescence Resonance Energy Transfer; Genes; Glycoproteins; HIV-1; Human; IFITM1 gene; Immune; Impairment; Infection; Integral Membrane Protein; Interferons; Mediating; Membrane Fluidity; Microscopy; Murine leukemia virus; Mutation; Osteogenesis; Physiological; Play; Process; Protein Family; Proteins; Proteomics; Publishing; Retroviridae; Role; Route; System; Therapeutic Intervention; Viral; Virion; Virus; Work; antiviral immunity; base; cell type; design; experimental study; gene therapy; in vivo; insight; mutant; novel; transmission process; tumorigenic

We published two articles pertaining to this project in 2020 (Ahi et al., mBio 11: e03088-19, 2020; Rahman et al., eLife 9: e58537, 2020). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. The focus of this project now is to understand the antiviral potential (or lack thereof) of other CD225 proteins encoded by humans, including IFITM5. IFITM5 is involved in bone formation and is not known to participate in antiviral immunity. We found that IFITM5 does not dimerize like its immune-related cousins (IFITM1, IFITM2, and IFITM3) and this is associated with a decreased capacity to impact membrane fluidity. Therefore, we provide an understanding of how related genes diverge following duplication and how antiviral activity is gained (or in this case, lost). Since most IFITM proteins possess the capacity to form homodimers, we are now in the process of characterizing how heterodimers contribute to their respective function. We are using unbiased proteomics and co-immunoprecipitation, and FRET-based microscopy to study the interaction of IFITM proteins with other cellular factors, and we are determining to what extent these interactions are consequential for their known antiviral functions. These results will also provide insight into the poorly characterized tumorigenic roles played by this family of proteins.

我们在2020年发表了两篇与该项目有关的文章(Ahi等人，mBio 11：e03088-19,2020；Rahman等人，eLife 9：e58537,2020)。我们的工作为IFITM蛋白及其所属的扩展CD225蛋白家族的功能提供了广泛的见解，并将为新的抗病毒疗法的开发提供杠杆作用。这个项目现在的重点是了解人类编码的其他CD225蛋白的抗病毒潜力(或缺乏)，包括IFITM5。IFITM5参与骨形成，但尚不清楚是否参与抗病毒免疫。我们发现IFITM5不像它的免疫相关表亲(IFITM1、IFITM2和IFITM3)那样二聚化，这与影响膜流动性的能力降低有关。因此，我们提供了对相关基因在复制后如何分化以及如何获得(或在这种情况下，失去)抗病毒活性的理解。由于大多数IFITM蛋白具有形成同源二聚体的能力，我们现在正在研究异源二聚体如何对其各自的功能做出贡献。我们正在使用无偏见的蛋白质组学和免疫共沉淀，以及基于FRET的显微镜来研究IFITM蛋白质与其他细胞因子的相互作用，我们正在确定这些相互作用在多大程度上对其已知的抗病毒功能产生影响。这些结果也将为深入了解这一蛋白家族所扮演的致癌作用提供依据。