Modulation of Influenza Virus Replication and Fitness by Adenosine Deaminases

 描述(申请人提供)：甲型流感病毒(IAV)是人类的一种上呼吸道病原体，可引起季节性流行和零星流行。IAV以其混杂宿主物种嗜好而闻名，可感染水禽、家禽、猪、人类和海洋哺乳动物。水禽和家畜特有的IAV毒株能够自发跨越物种障碍，导致其他宿主物种爆发，甚至在人类中大流行。IAV快速适应新环境的能力在一定程度上是由于编码的RNA依赖RNA聚合酶(RDRP)固有的低保真度；然而，关于宿主RNA编辑酶如何促进IAV进化的研究鲜为人知。我们最近确定ADAR1是一种宿主因子，对于IAV的最佳复制和在抗病毒药物(奥司他韦)选择期间维持病毒种群的适合性是必不可少的。这项建议旨在确定ADAR1编辑病毒基因组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趋向性。从这项研究中获得的知识将使我们能够(1)监测禽类储存库中可能跨越物种屏障的特定遗传多态，(2)确定可导致耐药性的季节性毒株中的遗传变异，(3)了解宿主适应突变的正选择是如何在自然进化过程中产生的，(4)确定宿主因素如何影响病毒的物种趋向性，(5)进一步研究其他编辑酶在RNA病毒进化中的作用，以及(6)开发针对宿主的疗法来抑制病毒的复制和适应。

 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.