Identification of interferon stimulated genes that restrict cross-species transmission of influenza A virus.

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Influenza A virus (IAV) is a major pathogen affecting many species, including humans, pigs and chickens. Seasonal epidemic outbreaks cause significant disease and death in humans, while pandemic outbreaks pose more catastrophic consequences as reflected by the 1918 Spanish Flu outbreak that resulted in more than 40 million deaths. Outbreaks of "bird flu" and "swine flu" result in large scale food production losses, resulting in severe strain on the world economy.The natural host of IAV is aquatic birds, like ducks, where the virus causes few signs of disease. However, IAV is able to jump to new species, where it can cause more severe symptoms. The occurrence of viral jumps from one species to another is relatively rare due to the difficulty of adapting to a new species. The host interferon (IFN) response represents a major barrier to this occurring.IFN is a protein released by cells in response to a virus infection. Once secreted, IFN binds to receptors of surrounding cells and triggers production and activation of hundreds of antiviral genes. Viruses that are well adapted to the host cell have evolved multiple mechanisms to counteract the IFN response, enabling efficient virus replication. However, these counter-measures can be less effective when the virus jumps to a new host, due to evolutionary divergence of antiviral genes. For a virus to successfully jump to a new species it must adapt through mutation of its genome to counteract the host IFN response, allowing efficient replication and ultimately spread through the population.While much work has focused on understanding the IFN system in human cells, less attention has been paid to other species. The flow of IAV between poultry, pigs and humans underlies pandemic outbreaks by aiding exchange of genetic material between viruses adapted to these species. Understanding the IFN response in pigs and chickens and the viral adaptations required when switching between these hosts is therefore crucial to evaluating the pandemic risks associated with specific strains of IAV.While the antiviral nature of IFN has long been documented, the specific mechanisms of how IFN inhibits different viruses is poorly understood. Recently, more than 500 human genes induced by IFN have been individually cloned, allowing overexpression and investigation of their effects on multiple viruses. This has proven to be a particularly powerful approach, resulting in significant discoveries on the action of IFN in human cells.In this application, we propose generating similar libraries of pig and chicken genes upregulated by IFN to evaluate their effects on IAV. In addition, we will evaluate the inhibitory effects of these genes in cross-species studies, by overexpressing antiviral genes from one species, in the cells of another, to determine their ability to inhibit strains of IAV adapted to specific host species. We predict that these studies will significantly contribute to our understanding of the IFN response in pigs and chickens, identify genes that are important for inhibiting IAV replication in pigs and chickens and identify IFN genes that represent barriers to IAV jumping from one host species to another. Finally, the generation of these libraries will also be highly valuable for future studies on how the IFN response effects other important pig and chicken pathogens.