猪繁殖与呼吸综合征病毒通过DNA甲基化限制IRF3上调表达的机制及其在先天性抗病毒免疫中的作用

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is an infectious pathogen that causes highly significant losses to the swine industry worldwide. During the process of interaction of PRRSV with host, PRRSV has evolved numbers of mechanisms by which PRRSV evades host immune defense. Among them, inhibition of production of type I interferon is crucial for evasion of host defense by PRRSV infections. Furthermore, several studies have shown that some of mechanisms by which PRRSV infections inhibit production of type I interferon are attribute to deactivation of interferon regulator factor 3 (IRF3) under the stimulation of poly(I:C). Furthermore, as the key regulator of type I interferon production, transcription of IRF3 also play an important role in regulation of production of type I interferon. As far, whether or not PRRSV infections inhibit production of type I interferon by modulation of IRF3 remains unknown. Our preliminary data show that decrease of DNA methylation up-regulates IRF3 and its downstream targets, type I interferon. Furthermore, decrease of DNA methylation significantly inhibits replication of virus. Thus, our preliminary data demonstrate that PRRSV infection could negatively regulate IRF3-dependent innate antiviral immune response by DNA methylation. To further clarify the molecular mechanisms by which PRRSV infections dampen host innate immune defense, our study focuses on the role of DNA methylation in modulation of IRF3 transcription, to determine the mechanisms by which PRRSV infections hamper induction of IRF3, and further dampen IRF3-dependent innate antiviral immune response. Collectively, the results of this study provide a basis of understanding the mechanisms of evasion of innate host defense by PRRSV and development of new therapeutic drugs to control PRRSV infection.

猪繁殖与呼吸综合征病毒（PRRSV）是危害养猪业生产的重要传染性病原。该病原在与宿主相互作用中已演化了突破宿主先天性抗病毒免疫防御机制，其中抑制I型干扰素产生是关键。IRF3作为调控I型干扰素产生的关键因子，PRRSV感染可抑制poly(I:C)诱导的IRF3激活。然而，是不是PRRSV感染通过调控IRF3转录抑制I型干扰素产生还不清楚。我们初步研究显示降低DNA甲基化显著上调IRF3及I型干扰素表达，进一步，抑制PRRSV复制。因此，该结果表明PRRSV感染通过DNA甲基化负调控IRF3依赖的先天性抗病毒反应。为了明确PRRSV感染通过DNA甲基化限制先天性抗病毒机制，本研究聚焦于DNA甲基化对IRF3的表达调控，揭示PRRSV感染通过DNA甲基化限制IRF3表达及负调控其依赖的先天性抗病毒机制。该研究不仅将丰富对PRRSV突破宿主先天性抗病毒的理解，还为新型抗病毒药物研发奠定理论基础。

.猪呼吸与繁殖综合征病毒（PRRSV）是危害世界养猪业生产的重要传染性病原。该病原在与宿主作用过程中已演化出了突破宿主先天性抗病毒免疫防御的机制，其中抑制I型干扰素产生是关键。IRF3作为调控I型干扰素产生的关键因子，PRRSV感染可抑制ploy(I:C) 诱导的IRF3激活。然而，是否PRRSV感染通过调控IRF3转录抑制I型干扰素的产生还不清楚。我们初步的研究显示降低DNA甲基化可显著上调IRF3及I型干扰素表达，进一步，抑制PRRSV复制。为了明确PRRSV感染通过DNA甲基化修饰限制先天性抗病毒机制，本研究聚焦于DNA甲基化对IRF3的表达调控，揭示PRRSV感染通过DNA甲基化修饰限制IRF3表达及负调控其依赖的先天性抗病毒机制，主要的结论包括：.1．.抑制DNA甲基化可以诱导宿主I型干扰素产生和限制PRRSV在猪肺泡巨噬细胞中复制。.2．.PRRSV侵染猪肺泡巨噬细胞可以导致Dnmt1上调表达。.3．.由Dnmt1调控的I型干扰素表达可以影响PRRSV感染。.4．.由Dnmt1介导的DNA甲基化可以抑制IRF3上调表达，影响I型干扰素表达进而促进PRRSV感染。.5．.在PRRSV侵染的猪肺泡巨噬细胞中，抑制DNA甲基化，沉默IRF3表达可以降低I型干扰素介导的先天性抗病毒反应。.6．.Dnmt1上调表达可提高IRF3 promoter区域DNA甲基化水平，进而调控IRF3介导的先天性抗PRRSV病毒反应。