Modulation of Influenza Virus Replication and Fitness by Adenosine Deaminases

 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。众所周知，它的混杂宿主种嗜性，IAV可以感染水禽，家禽，猪，人类和海洋哺乳动物。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。IAV快速适应新环境的能力部分是由于编码的RNA依赖性RNA聚合酶（RdRP）固有的低保真度;然而，对宿主RNA编辑酶如何促进IAV进化知之甚少。我们最近发现ADAR 1是一个宿主因子，在抗病毒药物选择（奥司他韦）过程中，ADAR 1对最佳IAV复制和维持病毒群体适应性至关重要。该提案旨在确定病毒基因组的ADAR 1编辑如何增加遗传多样性，推动进化，促进适应性，并有助于物种适应和组织向性。从这项研究中获得的知识将使我们能够（1）监测可能跨越物种屏障的禽类宿主中的特定遗传多态性，（2）鉴定季节性毒株中可能产生耐药性的遗传变异，（3）了解自然进化过程中宿主适应性突变的正选择如何发生，（4）确定宿主因素如何影响病毒的物种嗜性，（5）进一步研究其他编辑酶在RNA病毒进化中的作用，以及（6）开发靶向宿主的治疗剂以抑制病毒复制和适应。

 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.