Prrsv Infections Hamper Up-regulation Of IRF3 Via DNA Methylation,and Effect Of Which On IRF3-dependent Innate Antiviral Response

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)runder 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.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.Results presented in this thesis can be summarized as follows:1.Blockade of DNA methylation induces type I interferon responses and limits viral infections in PRRSV-infected macrophages.2.Up-regulation of Dnmtl is responsible for DNA methylation in PRRSV-infected macrophages.3.Dnmtl-regulated DNA methylation mediates modulation of type I interferon responses against PRRSV infection.4.Hampering up-regulation of IRF3,but not IRF7 through Dnmtl-regulated DNA methylation is linked to modulation of type I interferon responses against PRRSV infection.5.Knock-down of IRF3,but not IRF7 abolishes type I interferon-mediated antiviral response caused by inhibition of DNA methylation in PRRSV-infected macrophages.6.Up-regulation of Dnmtl contributes to maintain the level of IRF3 promoter methylation,which modulates IRF3-mediated antiviral response in PRRSV-infected macrophages.