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（由申请人证明）：流感病毒（IAV）是人类中的上流病原体，它是cass流行病和流行病[18-20]。和海乳房[21]。编码的RNA依赖性RNA聚合酶的固有物种与/或在感染新宿主时保持病毒适应性的态度是未知的[26，27]。通过（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IAV基因组RNA对复制和进化的ADAR1冥想的贡献，以及ADAR1-NS1相互作用的（3）在控制寄主物种的向流和促进适应性时，知识门研究将有助于阐明IAV篡夺宿主蛋白的原始功能，尤其是用于病毒进化和适应性还将导致新的监视方法，包括识别在其他物种中，NS1的亚型穿越了人体，f宿主指导的抗抗病性治疗方法可以在大流行状况中适应IAV适应宿主的能力。