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： 流感病毒是一个全球性的公共卫生问题，并有可能导致大流行。 虽然疫苗可以有效地保护个人免受流感病毒感染， 对防止疾病进展和病毒传播的抗病毒药物的巨大需求。因此，在本发明中， 需要努力研究流感病毒与宿主的相互作用，这对发展 抗流感病毒新药，包括广谱药物。像其他病毒一样， 流感病毒依赖于宿主细胞成分来完成病毒生命的大部分步骤 周期该项目的长期目标是确定控制细胞凋亡的关键宿主细胞蛋白质。 甲型流感病毒复制，使信息可用于开发新的 抗病毒药物流感病毒的NS 1蛋白是促进流感病毒传播的主要毒力因子 流感病毒复制通过对抗宿主抗病毒反应和调节各种 病毒复制的过程。NS 1蛋白在很大程度上发挥这些生理功能 通过与宿主细胞分子相互作用。通过定量蛋白质组学方法， 最近发现甲型流感病毒的NS 1蛋白与DEAD-box蛋白1相互作用 （DDX 1），一种假定的含有DEAD盒的RNA解旋酶。进一步的初步研究 DDX 1的敲除显著降低了甲型流感病毒在 人肺上皮细胞，表明DDX 1蛋白被甲型流感病毒“劫持”， 作为复制辅助因子。同时，敲低DDX 1导致显著的 在甲型流感病毒感染的细胞中，干扰素β mRNA水平降低，这表明它起着重要的作用。 在调节I型干扰素转录中的重要作用。两个具体目标将是 在这个项目中追求。目标1。研究DDX 1促进甲型流感的机制 病毒复制目标二。检查DDX调节干扰素β的机制 在甲型流感病毒感染的细胞中表达。这些结果将有助于理解 DDX 1在甲型流感病毒复制中的作用，提高对流感病毒的认识- 主机交互。研究结果可能有助于设计新的控制流感的策略 病毒感染