Modulation of Influenza Virus Replication and Fitness by Adenosine Deaminases

腺苷脱氨酶对流感病毒复制和适应性的调节

基本信息

批准号：
9090008
负责人：
Balaji Manicassamy
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CHICAGO
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：
2015-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090008
关键词：
ADAR1 Adenosine Antiviral Agents Birds Cell Line Cell physiology Cells Cytidine Cytidine Deaminase DNA Deaminase Dependence Development Disease Outbreaks Domestic Animals Double-Stranded RNA Enzymes Epidemic Epithelial Cells Evolution Family Family suidae Genomics HIV Health Hepatitis B Virus Hepatitis Delta Virus Homologous Gene Human Human Activities Human Herpesvirus 8 Infection Influenza Influenza A virus Inosine Integration Host Factors Knock-out Knowledge Lead Life Cycle Stages Lung Maintenance Mammals Measles Mediating Modeling Mus Mutate Mutation Nonstructural Protein Polymerase Process Protein Isoforms Proteins RNA Editing RNA Viruses RNA-Directed RNA Polymerase Regulation Research Respiratory Tract Infections Role Sea Single-Stranded DNA Staging Surveillance Methods Testing Therapeutic Tropism Uridine Viral Viral Genome Viral Proteins Virion Virus Virus Diseases Virus Replication adenosine deaminase domestic bird fitness genomic RNA in vivo influenzavirus knock-down knockout gene mutant novel overexpression pandemic disease pathogen recombinant virus reconstitution respiratory viral RNA viral fitness viral transmission

项目摘要

DESCRIPTION (provided by applicant): Influenza A virus (IAV) is an upper respiratory pathogen in humans that causes seasonal epidemics and sporadic pandemics[18-20]. Well known for its promiscuous host species tropism, IAV can infect waterfowl, domestic birds, swine, humans, and sea mammals[21]. IAV strains endemic to waterfowl and domestic animals are capable of spontaneously crossing the species barrier, leading to outbreaks in other host species and even pandemics in humans[22-25]. This adaptability is in part achieved through the inherent low fidelity of the encoded RNA dependent RNA polymerase; however, the host factors that contribute to efficient IAV transmission between species and/or maintain viral fitness upon infection of a new host remain unknown[26, 27]. We have recently identified ADAR1 as a host factor that is essential for optimal IAV replication and progeny fitness. We will further our understanding of the relationship between ADAR1 and IAV by (1) identifying and characterizing the mechanism(s) by which ADAR1 impacts influenza virus replication and progeny fitness, (2) determining the contribution of ADAR1 mediated editing of IAV genomic RNA to replication and evolution, and (3) investigating the role of ADAR1-NS1 interactions in controlling host species tropism and promoting adaptation. The knowledge gained from these studies will help to elucidate the mechanisms by which IAV usurps host proteins for proviral functions, particularly for viral evolution and adaptation, and allow us to apply these principals to other pathogenic viruses. This research will also lead to novel methods of surveillance, including identification of subtypes of NS1 in other species with the ability to cross the species barrier into humans. Furthermore, these studies will pave the way for development of host-directed antiviral therapeutics that can limit the capacity of IAV to adapt to new hosts during potentially pandemic situations.

描述（由申请人提供）：甲型流感病毒（IAV）是人类上呼吸道病原体，可引起季节性流行和散发性流行病[18-20]，其宿主物种混杂性广为人知，可感染水禽、家禽、猪、人类和海洋哺乳动物的 IAV 病毒株是水禽和家畜特有的，能够自发跨越物种屏障，导致疾病暴发。其他宿主物种，甚至人类的流行病[22-25]，这种适应性部分是通过编码的RNA依赖性RNA聚合酶固有的低保真度实现的；然而，有助于物种间有效IAV传播和/或维持的宿主因素。感染新宿主后的病毒适应性仍然未知[26, 27]，我们最近发现 ADAR1 是对于最佳 IAV 复制和后代适应性至关重要的宿主因子，我们将通过以下方式进一步了解 ADAR1 和 IAV 之间的关系。 (1) 识别和表征 ADAR1 影响流感病毒复制和后代适应性的机制，(2) 确定 ADAR1 介导的 IAV 基因组 RNA 编辑对复制和进化的贡献，以及 (3) 研究 ADAR1 的作用-NS1 在控制宿主物种趋向性和促进适应方面的相互作用，从这些研究中获得的知识将有助于阐明 IAV 侵占宿主蛋白的原病毒功能的机制，特别是病毒进化和适应的机制，并允许我们应用。这项研究还将带来新的监测方法，包括识别病毒。此外，这些研究将为开发针对宿主的抗病毒疗法铺平道路，这种疗法可以限制 IAV 在潜在大流行情况下适应新宿主的能力。