Understanding the mechanism of influenza A virus PB1-F2 immune signalling antagonism

禽流感对动物健康和粮食安全构成重大威胁。例如，自2003年以来，H5 N1流感已造成3亿多只鸡死亡。因此，更好地了解病毒与禽类宿主的相互作用对于改进控制策略至关重要。该项目将侧重于病毒基因组编码的辅助蛋白的作用。这些蛋白质对于体外病毒复制不是必需的，但可以调节体内致病性[1，2]。PB 1-F2是一种小的辅助蛋白，具有抑制干扰素反应的作用，其在禽流感分离株中比哺乳动物流感分离株中更高度保守。我们最近表明，根据病毒株，PB 1-F2可以抑制先天免疫信号传导，降低致病性并延长病毒脱落，延长鸡的传播窗口[2]。我们的假设是，A型流感病毒PB 1-F2蛋白已经进化到通过可变机制在禽类宿主中引起先天信号应答的抑制，并且这些差异部分解释了致病性。为了质疑这一假设，将研究以下问题：1。PB 1-F2中影响拮抗I型IFN或NF-kb（促炎性）信号通路的能力的病毒遗传决定因素是什么？利用这些不同机制的PB 1-F2蛋白的细胞相互作用组有什么不同？PB 1-F2蛋白在确定的病毒遗传星座内感染家禽期间的规定功能有多重要？

Avian influenza poses a major threat to animal health and food security. For instance, H5N1 influenza has been responsible for the deaths of over 300 million chickens since 2003. A better understanding of virus interactions with the avian host is therefore crucial to improve control strategies. This project will focus on the role of accessory proteins encoded by the virus genome. These proteins are non-essential for virus replication in vitro, but can modulate pathogenicity in vivo [1, 2]. PB1-F2 is a small accessory protein with a role in suppressing the inferferon response that is more highly conserved in avian than mammalian influenza isolates. We have recently shown that depending on virus strain, PB1-F2 can suppress innate immune signalling, decrease pathogenicity and lengthen viral shedding, extending the transmission window in chickens [2]. Our hypothesis is that influenza A virus PB1-F2 proteins have evolved to invoke suppression of innate signalling responses in avian hosts through variable mechanisms and that these differences partially explain pathogenicity. To interrogate this hypothesis the following questions will be studied; 1. What are the viral genetic determinants in PB1-F2 that influence the ability to antagonise the type I IFN or NF-kb (pro-inflammatory) signalling pathways? What are the differences in the cellular interactome for PB1-F2 proteins that utilise these different mechanisms? How important are the prescribed functions of a PB1-F2 protein during infection of poultry within a defined viral genetic constellation?