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：
9925203
负责人：
Balaji Manicassamy
金额：
$ 35.9万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-06 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925203
关键词：
ADAR1 Address Adenosine Antiviral Agents Avian Influenza A Virus Biological Assay Birds Cells Chemicals Data Dependence Disease Outbreaks Domestic Animals Dose Drug resistance Environment Enzymes Epidemic Evolution Family suidae Frequencies Genetic Polymorphism Genetic Variation Genome Genomics Guanosine Human Induced Mutation Influenza A Virus, H5N1 Subtype Influenza A virus Inosine Integration Host Factors Knowledge Maintenance Mammals Messenger RNA MicroRNAs Monitor Morbidity - disease rate Mus Mutagens Mutation Nonstructural Protein Oseltamivir Pathogenesis Pathogenicity Polymerase Population Population Genetics Population Heterogeneity Protein Isoforms RNA Editing RNA Viruses RNA-Directed RNA Polymerase Reading Research Resistance Role Sea Serial Passage System Tropism Vaccines Variant Viral Viral Genome Viral Proteins Virion Virulence Virus Virus Replication adenosine deaminase bioinformatics pipeline deep sequencing domestic bird dsRNA adenosine deaminase experimental study fitness genetic variant in vivo influenzavirus mortality pandemic disease pathogen pressure prevent public health relevance recombinant virus resistance mutation respiratory reverse genetics targeted treatment tissue tropism viral RNA viral fitness

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. Well known for its promiscuous host species tropism, IAV can infect waterfowl, domestic birds, swine, humans, and sea mammals. 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. The ability of IAV to rapidly adapt to new environments is in part due to the inherent low fidelity of the encoded RNA dependent RNA polymerase (RdRP); however, little is known as to how host RNA editing enzymes contribute to IAV evolution. We have recently identified ADAR1 as a host factor that is essential for optimal IAV replication and maintenance of viral population fitness during antiviral drug selection (oseltamivir). This proposal aims to determine how ADAR1 editing of the viral genome increases genetic diversity, drives evolution, promotes fitness, and contributes to species adaptation and tissue tropism. The knowledge gained from this research will allow us to (1) surveil for specific genetic polymorphisms in avian reservoirs that can potentially cross the species barrier, (2) identify genetic variants in seasonal strains that can render drug resistance, (3) understand how positive selection of host adaptive mutations arise during natural evolution, (4) determine how host factors influence viral species tropism, (5) further investigate the role of other editing enzymes n RNA virus evolution, and (6) develop host-targeted therapeutics to inhibit virus replication and adaptation.

描述（由申请人证明）：流感病毒（IAV）是人类的上层病原体，它以疾病的宿主物种tropism闻名水禽和国内的特有能力自发地易碎，导致OST物种爆发，甚至人类的大流行病。）。从re骨后CH将使我们能够（1）在鸟类储层中监视特定的遗传多态性，（2）季节性菌株可以使耐药性抗药性，（3）了解宿主自适应突变进化的积极选择，（4）确定如何确定宿主会影响病毒物种偏向主义6）发展宿主的治疗剂，以使病毒复制和适应。