New Paradigms in Gene Regulation During Influenza Virus Infections

描述（由申请人提供）：本项目的长期目标是了解流感病毒感染后人肺细胞中先天性抗病毒反应的调节机制和特异性介质。关于通过先天免疫系统的细胞病毒检测和伴随细胞和全身反应的获得的诱导基因表达事件，一般已知很多。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抗性的变异性。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在感染的主要部位的基因表达的转录后调节。该应用旨在阐明基础研究和临床方法对流感病毒感染的先天细胞反应的新范例。一个具体的目标将检查的假设，转录后基因调控调节典型的抗病毒基因表达程序在流感感染，并将破译细胞因子和病毒诱导的microRNA的作用，通过检查它们的生物发生和活性在感染的肺细胞系。第二个目的是检验以下假设：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流感临床表现的严重程度有关。将在人流感感染的急性期和恢复期分析气道粘膜样本的转录组，以鉴定与严重流感感染相关的新基因表达模式和途径。此外，对易患严重流感的患者和经历过较轻疾病的患者的气道粘膜转录组进行比较，将确定与流感感染易感性相关的新基因表达模式和途径。这些目标将共同阐明新的基本先天免疫机制，提供更复杂的了解抗病毒反应，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.