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先天抗病毒反应的调控机制和特定介质。关于先天免疫系统对细胞病毒的检测，以及伴随细胞和全身反应获得的可诱导基因表达事件，目前已知很多。然而，个体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变异性。这些差异反应是许多因素的结果，包括可变的转录反应或转录后的基因表达调控在感染的原发部位。本应用程序旨在阐明流感病毒感染的先天细胞反应的新范式，包括基础研究和临床方法。一个特定的目标将检验在流感感染期间转录后基因调控典型抗病毒基因表达程序的假设，并将通过检测感染肺细胞系中细胞因子和病毒诱导的microrna的生物发生和活性来破译它们的作用。第二个目的是检验一种假设，即流感病毒感染的主要部位——气道粘膜中的差异基因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，将分析气道粘膜样本的转录组，以确定与严重流感感染相关的新的基因表达模式和途径。此外，比较那些易患严重流感的人和那些经历过轻微疾病的人之间的气道粘膜转录组，将确定与流感感染易感性相关的新的基因表达模式和途径。总之，这些目标将阐明新的基本先天免疫机制，提供对抗病毒反应更复杂的理解，以及抗病毒治疗的潜在新靶点。

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.