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.

项目摘要 该R01提案的主要目标是表征干扰素刺激的基因E74样ETS转录 因子1（ELF1），体内和体外，关于其在限制病毒感染中的作用。虽然数百 干扰素刺激的基因（ISGS）执行干扰素（IFN）的抗病毒功能，对于绝大多数， 分子机制仍然是一个谜。了解宿主因素抑制病毒的机制 感染可能导致新型的抗病毒策略。该项目建立在我们最近发表的发现中， ELF1在抑制流感病毒中表现出直接的抗病毒作用。由于最初发现，我们的初步数据 表明ELF1在多发病毒复制后起作用，并且是抗病毒的。在上皮细胞中，ELF1 转录调节了一个大多数基因的巨大程序，主要与IFN调节的基因不同。 ELF1不会向前喂食以产生IFN，并且即使没有 进一步的IFN信令。有趣的是，该程序的至少一部分赋予了对邻近细胞的保护。最后，我们 表明IAV感染期间鼠ELF1的局部敲低可显着增加病毒肺滴度，发病率， 和体内死亡率。这些结果为Elf1在IFN中的作用提出了一个新颖的概念打开了大门 反应：这种转录因子是炎症和先天抗病毒免疫的新型调节剂。在 此外，我们的数据增加了ELF1的抗病毒程序继续保护细胞免受病毒侵害的激动人心的可能性 即使在IFN暴露后的难治阶段感染，或者当IFN信号被病毒废除时 对手。该提案的主要技术创新是使用多功能工具 成像以研究病毒感染期间细胞亚细胞信号传导事件。我们目标的完成将有很大 通过表征一个新颖的转录抗病毒程序，对该领域的影响，该程序既广泛又有效，但是 与IFN不同。