New Paradigms in Gene Regulation During Influenza Virus Infections

描述(由申请人提供)：该项目的长期目标是了解流感病毒感染后人肺细胞中先天抗病毒反应的调节机制和特定媒介。关于先天免疫系统对细胞病毒的检测以及伴随细胞和系统反应的可诱导的基因表达事件，人们已经知道了很多。然而，单个宿主可以以病毒特异性或细胞特异性的方式表现出对感染的抵抗力的差异性。这些不同的反应是许多因素的结果，包括可变的转录反应或转录后对主要感染部位的基因表达的调节。这项应用旨在通过基础研究和临床方法阐明针对流感病毒感染的先天细胞反应的新范例。一个特定的目标将检验这一假设，即转录后基因调控在流感感染期间调节规范的抗病毒基因表达程序，并将通过检测细胞因子和病毒诱导的microRNAs在受感染的肺细胞系中的生物发生和活性来破译它们的作用。第二个目标将检验这样一个假设，即流感病毒感染的主要部位--呼吸道粘膜中差异基因的表达与人类流感临床表现的严重程度有关。在人类流感感染的急性期和恢复期，将分析呼吸道粘膜样本的转录本，以确定与严重流感感染相关的新基因表达模式和途径。此外，对易患严重流感的人和经历较轻疾病的人的呼吸道粘膜转录进行比较，将发现与流感感染易感性有关的新的基因表达模式和途径。结合这些目标，将阐明新的基本先天免疫机制，提供对抗病毒反应的更复杂的理解，并为抗病毒治疗提供潜在的新靶点。

DESCRIPTION (provided by applicant): The long term objective for this project is to understand the regulatory mechanisms and specific mediators of innate antiviral responses in human lung cells following influenza virus infections. Much is known in general about cellular virus detection by the innate immune system and the inducible gene expression events that accompany the acquisition of cellular and systemic responses. However, individual hosts can demonstrate variability in resistance to infection in a virus-specific or cell-specific fashion. These differential responses are the result of many factors including variable transcriptional responses or post- transcriptional regulation of gene expression at the primary site of infection. This application is designed to elucidate new paradigms for innate cellular responses to influenza virus infection with both basic research and clinical approaches. One specific aim will examine the hypothesis that post-transcriptional gene regulation modulates canonical antiviral gene expression programs during influenza infections, and will decipher the roles of cytokine- and virus-induced microRNAs by examining their biogenesis and activity in infected lung cell lines. A second aim will test the hypothesis that differential gene expression in the airway mucosa, the main site of influenza virus infection, relates to severity of clinical presentation of human influenza. Transcriptomes of airway mucosal samples will be analyzed during acute phase and convalescence of human influenza infections to identify novel gene expression patterns and pathways related to severe influenza infections. In addition, comparison of airway mucosal transcriptomes between those predisposed to severe influenza and those who experienced milder disease will identify novel gene expression patterns and pathways related to susceptibility to influenza infections. Together these aims will elucidate new fundamental innate immune mechanisms, provide a more sophisticated understanding of the antiviral response, and potential new targets for antiviral therapy.