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

甲型流感病毒（IAV）是影响包括人、猪和鸡在内的许多物种的主要病原体。季节性流行病爆发会导致人类重大疾病和死亡，而大流行病爆发则会造成更灾难性的后果，1918年西班牙流感爆发导致4000多万人死亡。“禽流感”和“猪流感”的爆发导致大规模的粮食生产损失，对世界经济造成严重的压力。IAV的天然宿主是水生鸟类，如鸭子，病毒很少引起疾病的迹象。然而，IAV能够跳跃到新的物种，在那里它可以引起更严重的症状。由于适应新物种的困难，病毒从一个物种跳到另一个物种的发生相对罕见。宿主的干扰素（IFN）反应代表了这一发生的主要障碍。IFN是细胞对病毒感染做出反应而释放的蛋白质。一旦分泌，IFN结合到周围细胞的受体，并触发数百个抗病毒基因的产生和激活。很好地适应宿主细胞的病毒已经进化出多种机制来抵消IFN应答，从而实现有效的病毒复制。然而，由于抗病毒基因的进化分歧，当病毒跳跃到新的宿主时，这些对策可能不太有效。一个病毒要成功地转移到一个新的物种，它必须通过基因组的突变来适应，以抵消宿主的干扰素反应，从而实现有效的复制，并最终在整个种群中传播。虽然许多工作都集中在了解人类细胞中的干扰素系统，但对其他物种的关注较少。IAV在家禽、猪和人类之间的流动通过帮助适应这些物种的病毒之间的遗传物质交换而成为大流行爆发的基础。因此，了解猪和鸡的干扰素反应以及在这些宿主之间切换时所需的病毒适应性对于评估与特定IAV株相关的大流行风险至关重要。虽然干扰素的抗病毒性质早已有据可查，但干扰素如何抑制不同病毒的具体机制知之甚少。最近，500多个人类基因诱导的干扰素已被单独克隆，允许过表达和调查其对多种病毒的影响。这已被证明是一个特别强大的方法，在IFN在人类cells.In此应用程序中，我们建议产生类似的库的猪和鸡的基因上调IFN来评估其对IAV的影响的行动导致重大发现。此外，我们将评估这些基因在跨物种研究中的抑制作用，通过在另一个物种的细胞中过表达来自一个物种的抗病毒基因，以确定它们抑制适应特定宿主物种的IAV菌株的能力。我们预测，这些研究将显着有助于我们了解猪和鸡的干扰素反应，确定基因，是重要的抑制猪和鸡的IAV复制，并确定干扰素基因，代表障碍IAV跳跃从一个宿主物种到另一个。最后，这些文库的产生也将是非常有价值的IFN反应如何影响其他重要的猪和鸡病原体的未来研究。

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.