猪伪狂犬病毒蛋白激酶US3抑制I型干扰素信号通路的作用和分子机制

猪伪狂犬病是由伪狂犬病毒（PRV）引起的急性传染病，可致仔猪神经症状和高死亡率，母猪繁殖障碍。2011年以来，我国PRV突破了传统疫苗的防护，产生高致病的变异强毒株，给养猪业造成巨大经济损失。我们前期研究发现PRV蛋白激酶US3可以降解I型干扰素（IFN-I）正调控因子Bclaf1，但又不仅仅依赖于Bclaf1发挥拮抗IFN-I信号通路的作用，提示其在PRV逃逸宿主天然免疫反应中的重要作用。本项目将采用生物化学、细胞生物学和病毒学的方法，深入探究US3在PRV感染细胞中抑制IFN-I应答的作用和分子机制，包括：1）研究US3激酶降解Bclaf1的作用和分子机制；2）探究US3激酶不依赖Bclaf1抑制IFN-I的分子机制。本课题成果将进一步揭示PRV突破宿主天然免疫防线的分子机制，为开发新型PRV疫苗或探索新的抗病毒药物提供理论参考。

Porcine pseudorabies caused by pseudorabies virus (PRV) is one of the most economically important viral diseases for the swine industry worldwide, which can cause neurological symptoms and high mortality in piglets and reproductive failure in sows. Since 2011, the highly pathogenic PRV strains have broken through the protection of traditional vaccines in China and occasionally were reported in humans. In our previous studies, we found that the protein kinase US3 of PRV can not only degrade the positive regulator of type I interferon (IFN-I), Bclaf1, but also suppress the IFN-I signaling pathway in a Bclaf1-indepented manner, suggesting the significant roles of US3 in evading the innate immune response. In this proposal we plan to elucidate the effect and molecular mechanism of US3 in suppressing IFN-I response pathways. Specifically, we will 1) investigate the inhibitory effect and molecular mechanisms by which US3 degrades Bclaf1; 2) explore the molecular mechanisms by which US3 antagonizes the IFN-I response pathways independent of Bclaf1. This work will provide new insights into the molecular mechanisms by which PRV breaks through the natural immune defense and new clues for new vaccine strategies/drugs against PRV.