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: 10162699
• 负责人: Meike Dittmann
• 金额: $ 16.58万
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162699
• 关键词: 2019-nCoV; Adenoviruses; Anti-Inflammatory Agents; Antiviral Agents; Biological Assay; Bone Marrow; COVID-19; Cells; Cellular Assay; Cessation of life; Chikungunya virus; Classification; DNA Viruses; Data; Disease; Disease Progression; Drug Design; Drug Targeting; Epithelial Cells; Event; Exhibits; Genes; Genetic Transcription; Goals; Health; Hematopoietic; Herpesvirus 1; Human poliovirus; Image; Immunohistochemistry; In Vitro; Infection; Inflammation; Influenza A virus; Innate Immune System; Integration Host Factors; Interferons; Lead; Longitudinal Studies; Lung; Maps; Mass Spectrum Analysis; Mediating; Microscopy; Modeling; Molecular; Morbidity - disease rate; Mus; Para-Influenza Virus Type 3; Parents; Phase; Predisposition; Publishing; RNA Viruses; Refractory; Role; Route; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Simplexvirus; Testing; Vaccinia virus; Viral; Viral Load result; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Wild Type Mouse; Yellow fever virus; airway inflammation; antiviral immunity; c-ets1 transcription factor; cell type; combat; experimental study; immunopathology; in vivo; innovation; knock-down; metabolomics; mortality; mouse model; novel; novel therapeutics; parent grant; programs; response; stem; tissue culture; tool; transcription factor

PARENT GRANT-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 本R 01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（ELF 1），在体内和体外，关于其在限制病毒感染的作用。虽然每天有数百个 干扰素刺激基因（ISG）执行干扰素（IFN）的抗病毒功能，对于绝大多数， 分子机制仍然是个谜。了解宿主因子抑制病毒的机制 感染可能导致新的抗病毒策略。该项目是建立在我们最近发表的发现， ELF 1在抑制甲型流感病毒方面表现出直接的抗病毒作用。从最初的发现开始，我们的初步数据 表明ELF 1在多轮病毒复制后起作用，并且具有广泛的抗病毒性。在上皮细胞中，ELF 1 转录调节数百个基因的庞大程序，大多数与IFN调节的基因不同。 ELF 1不前馈以产生IFN，并且即使在缺乏IFN的情况下也保留其强的抗病毒潜力。 更多IFN信号有趣的是，这个程序至少有一部分可以保护邻近的细胞。最后我们 显示在IAV感染期间鼠Elf 1局部敲低显著增加病毒肺滴度、发病率 和体内死亡率。这些结果为ELF 1在IFN-γ中的作用提出了一个新的概念。 反应：这种转录因子是一种新型的炎症和先天性抗病毒免疫调节因子。在 此外，我们的数据提出了一种令人兴奋的可能性，即ELF 1的抗病毒程序继续保护细胞免受病毒感染。 即使在IFN暴露后的难治期，或当IFN信号被病毒抑制时， 对手。本方案的主要技术创新点是使用了多功能的共焦高含量成像工具 成像以研究病毒感染期间的亚细胞信号传导事件。实现我们的目标将有重大意义。 对该领域的影响，通过表征一种新的转录抗病毒程序，这是广泛和有效的，但 不同于IFN。