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

• 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
• 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

 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（由申请方提供）：甲型流感病毒（IAV）是一种人类上呼吸道病原体，可引起季节性流行和散发性大流行[18-20]。众所周知，IAV具有混杂的宿主种嗜性，可感染水禽、家禽、猪、人和海洋哺乳动物[21]。水禽和家畜特有的IAV毒株能够自发地跨越物种屏障，导致在其他宿主物种中爆发，甚至在人类中流行[22-25]。这种适应性部分是通过编码的RNA依赖性RNA聚合酶的固有低保真度实现的;然而，有助于IAV在物种之间有效传播和/或在感染新宿主后维持病毒适应性的宿主因素仍然未知[26，27]。我们最近已经确定ADAR 1作为一个主机的因素，是必不可少的最佳IAV复制和后代的健身。我们将通过以下方式进一步了解ADAR 1与IAV之间的关系：（1）鉴定和表征ADAR 1影响流感病毒复制和子代适应性的机制，（2）确定ADAR 1介导的IAV基因组RNA编辑对复制和进化的贡献，以及（3）研究ADAR 1-NS 1相互作用在控制宿主物种嗜性和促进适应中的作用。从这些研究中获得的知识将有助于阐明IAV篡夺宿主蛋白质以实现前病毒功能的机制，特别是用于病毒进化和适应，并使我们能够将这些原理应用于其他致病性病毒。这项研究还将导致新的监测方法，包括识别 其他物种中的NS 1亚型具有跨越物种屏障进入人类的能力。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在潜在的大流行情况下适应新宿主的能力。