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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：小非编码 RNA 正在成为病毒感染的关键参与者，具有促进或限制病毒复制的多种作用，从而影响人类疾病。与 DNA 病毒感染相比，RNA 病毒之间的相互作用景观。该提案概述了在 RNA 病毒感染背景下分析小 RNA（特别是 miRNA）的动态和功能的综合程序。那对于病毒复制（如 miR-122 和 HCV）或宿主细胞生物学的调节很重要我们发现了 HCV RNA 功能性隔离 miR-122 的“海绵”效应，并且我们认为这可能代表了一种普遍机制。 RNA 病毒可以影响宿主基因表达以发挥其优势，我们还证明 miR-122 HCV 的故事并不是独一无二的，与 HCV 相比，瘟病毒也需要与宿主 miRNA 相互作用才能复制。 miR-122 的两个结合位点位于基因组 RNA 5' 端附近，牛病毒性腹泻病毒需要在 3'UTR 的种子位点结合 miR-17 家族成员，而该种子位点在瘟病毒中完全保守。激发了我们将这种搜索范围扩大到生物学相关性越来越高的广泛动物病毒的兴趣除了继续对丙型肝炎病毒和瘟病毒进行机制研究外，我们还将把这项工作扩展到两种具有医学意义的代表性虫媒病毒——西尼罗河病毒和基孔肯雅病毒，这些病毒将在蚊子和脊椎动物细胞培养物中进行研究，同时也在蚊子媒介和脊椎动物模型中进行研究。为了涵盖更具毒性的病原体，我们与亚特兰大疾病预防控制中心建立了合作，以检查一些高遏制病毒，其中包括丝状病毒埃博拉病毒和。这使得探索整个病毒属所需的新型宿主病毒相互作用（如肝炎病毒的 miR-122）成为可能，这些见解可以为治疗和预防重要的人类病毒提供新方法。感染。