Analysis of Novel Virus-Induced RNAs

 描述(申请人提供)：病毒感染人类细胞诱导快速和动态的基因表达，导致下游效应通路的激活，这些下游效应通路控制病毒复制，调节细胞死亡，并激活和教育随后的先天和适应性免疫反应。对病毒感染前后的主要抗病毒转录调控因子IRF3和NFκB、RNAPOL II和POL II相关的共同调控因子的分析揭示了抗病毒转录反应的新特征，导致了一个重要的假设，即新发现的病毒诱导的RNA产物和辅助转录调控因子代表了抗病毒免疫的新方面，有可能产生新型的抗病毒治疗和诊断工具。这些新的转录途径将在分子细节上进行研究，以揭示它们被具有生物医学意义的代表性RNA和DNA病毒，特别是仙台病毒、甲型流感病毒和单纯疱疹病毒诱导的程度。此外，还将确定它们由先天抗病毒信号通路诱导的能力以及它们在抗病毒免疫中的潜在功能。三个特定的目标将使用分子和生化实验来补充病毒学方法和RNA测序分析来研究新的病毒诱导的RNA的表达模式，以确定它们的结构、功能和对抗病毒免疫的贡献。此外，E-Box、Ets和CREB家族中被认为具有辅助抗病毒主调节作用的辅助转录因子将被分析，以确定它们在驱动病毒诱导转录和抗病毒反应方面的贡献。总之，这些研究将对新发现的、但以前被忽视的大量抗病毒反应者进行广泛而有针对性的分析，并将确定新的免疫控制病毒感染的功能和调节途径。

 DESCRIPTION (provided by applicant): Virus infection of human cells induces rapid and dynamic gene expression that leads to the activation of downstream effector pathways that control virus replication, regulate cell death, and activate and educate subsequent innate and adaptive immune responses. Analysis of master antiviral transcription regulators IRF3 and NFκB, RNA Pol II, and Pol II-associated co-regulators before and after virus infection has revealed new features of the antiviral transcriptional response, leading to an overarching hypothesis that newly recognized virus-induced RNA products and auxiliary transcription regulators represent new aspects of antiviral immunity that have the potential to produce novel classes of antiviral therapies and diagnostic tools. These new transcription pathways will be examined in molecular detail to reveal their extent of inducibility by biomedically significant representative RNA and DNA viruses, specifically Sendai virus, influenza A virus, and herpes simplex virus. In addition their inducibility by innate antiviral signaling pathways and their potential functions in antiviral immunity will be determined. Three specific aims will use molecular and biochemical experiments to complement virological approaches and RNA-sequencing analysis to investigate the expression patterns of novel virus-induced RNAs, to determine their structures, functions, and contributions to antiviral immunity. In addition, auxiliary transcription factors in the E-Box, ETS, and CREB families that were recognized as having a role in assisting antiviral master regulators will be analyzed to determine their contributions toward driving virus-induced transcription and antiviral responses. Together these studies will provide both a broad-based and focused analysis of a newly recognized but large pool of antiviral responders that has been previously overlooked, and will identify new functional and regulatory pathways for immune control of virus infections.