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.

家长助学金--项目摘要 这个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方面的作用。尽管数以百计的 干扰素刺激基因(ISGs)执行干扰素(干扰素)的抗病毒功能，对于绝大多数 分子机制仍然是个谜。了解宿主因素抑制病毒的机制 感染可能导致新的抗病毒策略。该项目是基于我们最近发表的发现而建立的 Elf1在抑制甲型流感病毒方面显示出直接的抗病毒作用。由于最初的发现，我们的初步数据 表明Elf1在多轮病毒复制后起作用，并具有广泛的抗病毒作用。在上皮细胞中，Elf1 转录调控一个由数百个基因组成的庞大程序，这些基因大多与干扰素调控的基因截然不同。 Elf1不能前馈产生干扰素，即使在缺乏干扰素的情况下仍保持其强大的抗病毒能力。 进一步的干扰素信号。有趣的是，该计划至少有一部分为邻近的细胞提供了保护。最后，我们 研究表明，在IAV感染期间，小鼠Elf1的局部敲除显著增加了病毒肺滴度，发病率， 以及活体内死亡率。这些结果为精灵1的S在干扰素中的角色提出了一个新的概念 回应：该转录因子是一种新的炎症和先天抗病毒免疫调节因子。在……里面 此外，我们的数据增加了Elf1的S抗病毒程序继续保护细胞免受病毒感染的令人兴奋的可能性 感染，即使在干扰素暴露后的难治期，或当干扰素信号被病毒取消时 对抗者。该方案的主要技术创新是使用了共焦高内容的多功能工具 研究病毒感染过程中亚细胞信号事件的成像技术。完成我们的目标将有重大的 对该领域的影响，通过表征一种新的转录抗病毒计划，该计划同样广泛和有效，但 有别于干扰素。