Modulation of Influenza Virus Replication and Fitness by Adenosine Deaminases

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 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.