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

了解甲型流感病毒PB1-F2免疫信号拮抗机制

• 批准号: 1991999
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1991999
• 关键词: Understanding; mechanism; influenza; virus; PB1

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?

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，H5N1流感已导致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。本项目将重点研究病毒基因组编码的辅助蛋白的作用。这些蛋白在体外对病毒复制不是必需的，但在体内可以调节致病性[1,2]。PB1-F2是一种小的辅助蛋白，在抑制干扰素反应中起作用，在禽类中比在哺乳动物流感分离株中更为高度保守。我们最近的研究表明，根据不同的病毒株，PB1-F2可以抑制先天免疫信号，降低致病性，延长病毒脱落，延长鸡[2]的传播窗口。我们的假设是，甲型流感病毒PB1-F2蛋白已经进化到通过不同的机制来抑制禽类宿主的先天信号反应，这些差异部分解释了致病性。为了验证这一假设，将研究以下问题；1. 什么是PB1-F2中影响对抗I型IFN或NF-kb（促炎）信号通路能力的病毒遗传决定因素？利用这些不同机制的PB1-F2蛋白的细胞相互作用组有什么不同？在确定的病毒遗传群中，PB1-F2蛋白在家禽感染期间的规定功能有多重要？