Role of RNA helicase DDX1 in influenza A virus replication

RNA解旋酶DDX1在甲型流感病毒复制中的作用

• 批准号: 10439323
• 负责人: Yuchun Du
• 金额: $ 43.07万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439323
• 关键词: A549; Abbreviations; Affect; Antiviral Agents; Antiviral Response; Cells; Complex; DDX1 gene; DDX1 protein; DNA-Directed RNA Polymerase; Data; Development; Disease Progression; Double-Stranded RNA; Epithelial; Epithelial Cells; Gene Expression; Genes; Genetic Transcription; Goals; Hour; Human; IRF3 gene; Immunoprecipitation; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Interferon Type I; Interferon-beta; Interferons; Life Cycle Stages; Light; Literature; Lung; Messenger RNA; Methods; Morbidity - disease rate; Nonstructural Protein; Periodicity; Pharmaceutical Preparations; Physiological; Play; Process; Production; Proteins; Proteomics; Public Health; Puerto Rico; Quantitative Reverse Transcriptase PCR; RNA; RNA Helicase; RNA Recognition Motif; Replication-Associated Process; Respiratory Disease; Role; Signal Transduction; Small Interfering RNA; Structure; TRIM25 gene; Testing; Time; Tretinoin; Vaccines; Viral; Viral Genome; Virulence Factors; Virus; Virus Diseases; Virus Replication; Western Blotting; base; cofactor; design; helicase; influenza infection; influenzavirus; knock-down; mortality; novel strategies; novel therapeutic intervention; novel therapeutics; pandemic disease; prevent; recruit; respiratory; sperm ganglioside 1; stress granule; therapeutic development; ubiquitin-protein ligase; viral RNA; viral transmission; virus host interaction

PROJECT SUMMARY: Influenza virus is a worldwide public health problem and has the potential to cause a pandemic. While vaccines can efficiently protect individuals from infection with influenza virus, there is still a great need for antiviral drugs that prevent disease progression and virus transmission. Thus, efforts are needed to study the influenza virus-host interactions, which are critical for developing novel drugs against the influenza virus, including broad-spectrum drugs. Like other viruses, influenza viruses depend on host cellular components to complete most steps of the viral life cycle. The long-term goal of this project is to identify the critical host cellular proteins that control influenza A virus replication, so that the information can be used for the development of new antiviral drugs. The NS1 protein of influenza virus is a major virulence factor that facilitates influenza virus replication through countering host antiviral response and regulating various processes in virus replication. The NS1 protein exerts these physiological functions largely through interacting with host cellular molecules. Through a quantitative proteomic method, it was recently found that the NS1 protein of influenza A virus interacts with DEAD-box protein 1 (DDX1), a putative DEAD-box-containing RNA helicase. Further preliminary studies demonstrate that knockdown of DDX1 dramatically reduces influenza A virus replication in human lung epithelial cells, suggesting that DDX1 protein is “hijacked” by influenza A virus and functions as a replication cofactor. Concomitantly, knockdown of DDX1 leads to significant decreases in interferon beta mRNA levels in influenza A virus infected cells, suggesting it plays an important role in regulating the transcription of type I interferons. Two specific aims will be pursued in this project. Aim 1. Examine the mechanism by which DDX1 facilitates influenza A virus replication. Aim 2. Examine the mechanisms by which DDX regulates interferon beta expression in influenza A virus-infected cells. The results will contribute to understanding the role of DDX1 in influenza A virus replication and enhance the understanding of influenza virus- host interactions. The results may shed light on designing novel strategies to control influenza viral infection.

项目概要： 流感病毒是一个世界性的公共卫生问题，有可能引起大流行。 虽然疫苗可以有效保护个人免受流感病毒感染，但仍然存在以下问题： 非常需要预防疾病进展和病毒传播的抗病毒药物。 需要研究流感病毒与宿主的相互作用，这对于发展至关重要 与其他病毒一样，针对流感病毒的新型药物包括广谱药物。 流感病毒依赖宿主细胞成分来完成病毒生命的大部分步骤 该项目的长期目标是确定控制细胞周期的关键宿主细胞蛋白。 甲型流感病毒复制，使信息可用于新药的开发 流感病毒的NS1蛋白是抗病毒药物的主要毒力因子。 通过对抗宿主抗病毒反应和调节各种机制来抑制流感病毒的复制 NS1 蛋白主要发挥这些生理功能。 通过定量蛋白质组学方法，它与宿主细胞分子相互作用。 最近发现甲型流感病毒的NS1蛋白与DEAD-box蛋白1相互作用 (DDX1)，一种假定的含有 DEAD-box 的 RNA 解旋酶。 证明 DDX1 的敲除可显着减少甲型流感病毒的复制 人肺上皮细胞，表明 DDX1 蛋白被甲型流感病毒“劫持”， 同时，DDX1 的敲低会导致显着的复制辅助因子。 甲型流感病毒感染细胞中干扰素 β mRNA 水平下降，表明它发挥作用 调节 I 型干扰素转录的重要作用是两个具体目标。 本项目追求的目标 1. 检查 DDX1 促进甲型流感的机制。 目标 2. 检查 DDX 调节干扰素 β 的机制。 甲型流感病毒感染细胞中的表达结果将有助于理解甲型流感病毒感染的细胞中的表达。 DDX1在甲型流感病毒复制中的作用并增强对流感病毒的了解- 这些结果可能有助于设计控制流感的新策略。 病毒感染。