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[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.