A systematic analysis of small RNA interactions during RNA virus infections

RNA病毒感染过程中小RNA相互作用的系统分析

• 批准号: 9191337
• 负责人: Charles M Rice
• 金额: $ 54.51万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191337
• 关键词: 3' Untranslated Regions; Animals; Antiviral Agents; Arboviruses; Arthropods; Binding; Binding Sites; Biochemical; Biological; Bovine Viral Diarrhea Viruses; Cell Culture Techniques; Cells; Cellular biology; Centers for Disease Control and Prevention (U.S.); Chikungunya virus; Collaborations; Collection; Containment; Culicidae; DNA Viruses; Data; Dependence; Development; Ebola virus; Environment; Evaluation; Family; Family member; Filoviridae; Filovirus; Flavivirus; Frankfurt-Marburg Syndrome Virus; Gene Expression; Genome; Goals; Health; Hepacivirus; Hepatitis C; Human; Immune response; Immune system; Immunoprecipitation; In Vitro; Infection; Lead; Link; Liver; Maps; Medical; Methods; MicroRNAs; Modeling; Molecular; Nucleic Acids; Pathogenesis; Pestivirus; Play; Porifera; Prevention; Process; Proteins; RNA; RNA Binding; RNA Interference; RNA Stability; RNA Virus Infections; RNA Viruses; RNA replication; Regulatory Pathway; Role; Seeds; Site; Small RNA; System; Systems Analysis; Technology; Testing; Ticks; Transcript; Translations; Untranslated RNA; Variant; Vertebrates; Viral; Viral Genes; Virulent; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; base; crosslink; deep sequencing; experimental study; functional genomics; human disease; immune RNA; in vivo; insight; interest; new therapeutic target; novel; novel strategies; pathogen; prevent; programs; public health relevance; screening; therapeutic target; tool; transcriptome; vector mosquito; viral RNA; virology; virus host interaction

 DESCRIPTION (provided by applicant): Small non-coding RNAs are emerging as key players in virus infections, with numerous roles to promote or restrict viral replication and thereby impac human disease. In contrast to infections with DNA viruses, the interaction landscape between RNA viruses and host cell small RNAs is poorly characterized. This proposal outlines a comprehensive program to analyze the dynamics and function of small RNAs, in particular miRNAs, in the context of RNA virus infections. Our focus is on defining functional interactions between cellular miRNAs and viral RNAs that are important for virus replication (like miR-122 and HCV) or modulation of host cell biology. We have uncovered a "sponge" effect in which HCV RNA functionally sequesters miR-122, and we hypothesize that this may represent a general mechanism by which RNA viruses can influence host gene expression to their advantage. We have also demonstrated that the miR-122 HCV story is not unique-rather pestiviruses also require interaction with a host miRNA for replication. In contrast to HCV and miR-122 with its two binding sites near the 5' end of genome RNA, bovine viral diarrhea virus requires binding of miR-17 family members at a seed site in the 3'UTR that is completely conserved among pestiviruses. These strong preliminary data have kindled our interest in expanding this search to a broad collection of animal viruses in increasingly biologically relevant systems. Besides continuing mechanistic studies on HCV and the pestiviruses, we will expand this effort to two representative arboviruses of medical importance-West Nile virus and chikungunya virus. These will be studied in mosquito and vertebrate cell cultures but also in mosquito vectors and vertebrate models. To encompass more virulent pathogens, we have established a collaboration with the CDC in Atlanta to examine a number of high containment viruses, including, among others, the filoviruses Ebola and Marburg viruses, and tick-borne flaviviruses. This exploration holds the promise of uncovering novel host-virus interactions required for entire virus genera (like miR-122 for the hepaciviruses), insights that could provide new approaches for treatment and prevention of important human viral infections.

 描述（由适用提供）：小型非编码RNA正在成为病毒感染的关键参与者，在促进或限制病毒复制并从而造成人类疾病的角色众多。与DNA病毒感染相反，RNA病毒和宿主细胞小RNA之间的相互作用景观的特征很差。该提案概述了一个综合计划，以分析RNA病毒感染的背景下，分析小RNA，特别是miRNA的动态和功能。我们的重点是定义对病毒复制至关重要的细胞miRNA和病毒RNA之间的功能相互作用（例如miR-122和HCV）或宿主细胞生物学的调节。我们发现了一种“海绵”效应，其中HCV RNA在功能上隔离miR-122，我们假设这可能代表了一种一般机制，通过该机制，RNA病毒可以通过该机制影响宿主基因的表达来提高其优势。我们还证明，miR-122 HCV的故事不是独特的 - 暂存病毒，还需要与宿主miRNA相互作用进行复制。与HCV和MiR-122及其在基因组RNA的5端附近的两个结合位点相比，牛病毒腹泻病毒需要在3'UTR的种子位点上MiR-17家族成员在Pestiviruse中完全保守的MiR-17家族成员。这些强大的初步数据激发了我们对将这种搜索扩展到越来越多的生物学相关的广泛动物病毒的兴趣 系统。除了对HCV和PESTIVIRUS的持续机械研究外，我们还将将这项工作扩展到两个具有医学重要性的代表性的Arbovires-West-West-West-West-West-West Nile病毒和Chikungunya病毒。这些将在蚊子和脊椎动物细胞培养物中进行研究，还将在蚊子和脊椎动物模型中进行研究。为了涵盖更多毒的病原体，我们已经与亚特兰大的CDC建立了合作，以检查许多高遏制病毒，包括埃博拉病毒埃博拉病毒和马尔堡病毒，以及tick骨出生的黄素病毒。这种探索有望揭示整个病毒属所需的新型宿主病毒相互作用（例如肝病病毒的miR-122），这些见解可以为治疗和预防重要的人类病毒感染提供新的方法。