ELF1 - Molecular mechanisms of a novel transcription factor with broad antiviral activity

ELF1 - 具有广泛抗病毒活性的新型转录因子的分子机制

• 批准号: 10200184
• 负责人: Meike Dittmann
• 金额: $ 3.42万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-18 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200184
• 关键词: Adenoviruses; Affect; Antiviral Agents; Antiviral Therapy; Biological; Biological Assay; Biology; Bone Marrow; Cells; Cellular Assay; Cessation of life; Chikungunya virus; Classification; Crohn' s disease; DNA Viruses; Data; Disease; Disease Outcome; Disease Progression; Drug Design; Drug Targeting; Epithelial Cells; Event; Exhibits; Gene Expression; Genes; Genetic Transcription; Goals; Health; Hematopoietic; Herpesvirus 1; Human poliovirus; Image; Immune; Immunohistochemistry; In Situ Hybridization; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Influenza A virus; Innate Immune System; Integration Host Factors; Interferon Type I; Interferons; Knowledge; Lead; Longitudinal Studies; Lung; Maps; Mass Spectrum Analysis; Mediating; Microscopy; Modeling; Molecular; Morbidity - disease rate; Mus; Para-Influenza Virus Type 3; Phase; Physiological; Predisposition; Publishing; RNA; RNA Viruses; Refractory; Role; Route; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Simplexvirus; Systemic Lupus Erythematosus; Testing; Time; Vaccinia virus; Viral; Viral Load result; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Wild Type Mouse; Work; Yellow fever virus; antiviral immunity; c-ets1 transcription factor; cell type; combat; cytokine; experimental study; genetic association; in vivo; inhibitor/antagonist; innovation; knock-down; metabolomics; mortality; mouse model; novel; novel therapeutics; programs; response; stem; tool; transcription factor

PROJECT SUMMARY The primary goal of this R01 proposal is to characterize the interferon-stimulated gene E74-like ETS transcription factor 1 (ELF1), in vivo and in vitro, regarding its role in restricting virus infections. Although hundreds of interferon-stimulated genes (ISGs) execute the antiviral function of interferon (IFN), for the vast majority, the molecular mechanisms remain a mystery. Understanding the mechanisms by which host factors inhibit viral infections may lead to novel antiviral strategies. The project is founded on our recent published discovery that ELF1 exhibits direct antiviral action in inhibiting influenza A virus. Since that initial discovery, our preliminary data show that ELF1 acts after multiple rounds of viral replication and is broadly antiviral. In epithelial cells, ELF1 transcriptionally regulates a vast program of hundreds of genes mostly distinct from those regulated by IFN. ELF1 does not feed forward to produce IFN, and retains its strong antiviral potential even in the absence of further IFN signaling. Intriguingly, at least part of this program confers protection to neighboring cells. Finally, we show that local knockdown of murine Elf1 during IAV infection significantly increases viral lung titers, morbidity, and mortality in vivo. These results opened the door to propose a novel concept for ELF1's role in the IFN response: that this transcription factor is a novel regulator of inflammation and innate antiviral immunity. In addition, our data raise the exciting possibility that ELF1's antiviral program continues protecting cells from viral infections even in the refractory phase post IFN exposure, or when IFN signaling is abrogated by viral antagonists. The main technical innovation of this proposal is the use the versatile tool of confocal high-content imaging to study sub-cellular signaling events during viral infections. Completion of our aims will have major impact on the field, by characterizing a novel transcriptional antiviral program that is as broad and potent, but distinct from IFN.

项目概要 该 R01 提案的主要目标是表征干扰素刺激基因 E74 样 ETS 转录 因子 1 (ELF1)，在体内和体外，关于其在限制病毒感染中的作用。尽管数百 干扰素刺激基因 (ISG) 执行干扰素 (IFN) 的抗病毒功能，绝大多数情况下， 分子机制仍然是个谜。了解宿主因素抑制病毒的机制 感染可能会导致新的抗病毒策略。该项目是基于我们最近发表的发现 ELF1 在抑制甲型流感病毒方面表现出直接的抗病毒作用。自从最初的发现以来，我们的初步数据 表明 ELF1 在多轮病毒复制后起作用，并且具有广泛的抗病毒作用。在上皮细胞中，ELF1 转录调节由数百个基因组成的庞大程序，这些基因大多与 IFN 调节的基因不同。 ELF1 不会前馈产生 IFN，即使在缺乏 IFN 的情况下仍保留其强大的抗病毒潜力 进一步的干扰素信号传导。有趣的是，该计划的至少一部分为邻近的小区提供了保护。最后，我们 表明在 IAV 感染期间局部敲低小鼠 Elf1 显着增加病毒肺滴度、发病率、 和体内死亡率。这些结果为提出 ELF1 在 IFN 中的作用的新概念打开了大门 反应：该转录因子是炎症和先天抗病毒免疫的新型调节剂。在 此外，我们的数据提出了令人兴奋的可能性，即 ELF1 的抗病毒程序将继续保护细胞免受病毒侵害 即使在 IFN 暴露后的难治期，或者当 IFN 信号被病毒消除时，感染 对手。该提案的主要技术创新在于使用共焦高内涵的多功能工具 成像研究病毒感染期间的亚细胞信号传导事件。完成我们的目标将有重大意义 通过描述一种广泛而有效的新型转录抗病毒程序，对该领域产生了影响，但 与干扰素不同。