猪瘟病毒诱导STAT1上调的分子机制探索

Classical swine fever (CSF) is one of the most important infectious diseases of pigs caused by classical swine fever virus (CSFV), to explore its pathogenesis and immune response mechanism is a pivotal point for prevention and control of the disease. Signal transducer and activator of transcription 1 (STAT1) plays a crucial role in the antiviral immune response usually stimulated by interferon after virus infection. We found that CSFV virulent strain inhibits type I interferon（IFN-α/β）expression, but significantly up-regulate mRNA level and protein expression of STAT1 in the porcine kidney cell line PK-15, implicating that CSFV may have another special way to up-regulate STAT1, which possibly plays a key role in the virus evasion from the host immune system. Consequently, in this study our group based on the models of swine PBMC in vivo and porcine alveolar macrophage 3D4/2, porcine kidney epithelial cells PK-15 in vitro after CSFV infection, including highly virulent strain (Shimen) and attenuated vaccine strain (C-strain), attempt to explore how CSFV influences on STAT1 expression, find which CSFV protein promotes STAT1 up-regulation, elucidate molecular pathway of CSFV stimulates STAT1—that is the molecular mechanism how CSFV inhibits type I interferon while up-regulates the level of STAT1, and then further to illuminate the influence over-expression of STAT1 on replication and transcription of CSFV. These data will provide theoretical foundation for elucidating the interaction mechanism between CSFV and host, further to developing new vaccine and screening drug target against CSFV.

猪瘟是由猪瘟病毒（CSFV）引起猪最重要的传染病之一，探索该病的致病机理和免疫应答机制是防控该病的关键环节。信号转导及转录激活因子1（STAT1）在病毒感染后主要由干扰素刺激产生，在抗病毒免疫应答中起着至关重要的作用。我们发现在猪肾细胞PK-15中CSFV强毒株可抑制I型干扰素的表达，却能刺激STAT1的上调，说明CSFV可能通过一条特殊途径来激活STAT1，可能对病毒逃逸机体免疫应答起到关键作用。本研究以CSFV强弱毒株感染猪体内外周血淋巴细胞和体外猪肺泡巨噬细胞3D4/2、PK-15为模型，探索CSFV对STAT1表达的影响，寻找CSFV中引起STAT1上调的病毒蛋白；阐明CSFV在抑制I型IFN表达的情况下如何刺激STAT1上调的分子机制; 进一步探索STAT1对CSFV复制与转录的影响，为阐明CSFV与宿主互作机制提供理论数据，为抗猪瘟病毒新型疫苗的研制和药物靶标筛选提供理论依据。

猪瘟（CSF）是猪最重要的传染病之一，探索该病的致病机理和免疫应答机制是防控的关键。信号转导及转录激活因子1（STAT1）在病毒感染后主要由干扰素刺激产生，在抗病毒免疫应答反应中起着至关重要的作用。我们证实在猪肾细胞PK-15中CSFV强毒能抑制IFNα/β的表达，却能刺激STAT1的上调与核转移，是通过病毒的结构蛋白Erns/E1/E2来实现的；猪瘟病毒通过非IFNα/β、TLR4、RIG1、IL-6、IL-12途径上调STAT1；无论是先干扰后接毒，还是先接毒后干扰，都显示干扰STAT1的表达对抑制猪瘟病毒的gRNA、蛋白表达和子代病毒的形成有显著的影响，说明Stat-1卷入了猪瘟病毒的复制，这些研究结果为阐明猪瘟病毒的致病机理、病毒如何利用宿主抗病毒机制提供理论依据。