病毒感染触发天然免疫反应以及病毒如何通过负向调控天然免疫反应而逃逸免疫的机制是分子免疫领域的前沿热点。转录因子IRF3促进Ⅰ类干扰素转录进而在防御病毒感染过程中起关键作用，因此其活化受到严格调控，大量研究揭示了其活化及失活过程，但其详细的调控过程仍未完全揭示。我们通过cDNA芯片筛选VSV病毒感染前后小鼠腹腔巨噬细胞的差异基因，发现蛋白甲基化转移酶Smyd2 mRNA在病毒刺激后表达显著降低，RNA干扰巨噬细胞的Smyd2表达，发现Ⅰ类干扰素产生显著升高.通过制备Smyd2-/-小鼠，并且体内感染VSV，证实Smyd2抑制Ⅰ类干扰素产生,从而抑制病毒的清除。进一步Western blot检测发现IRF3的磷酸化显著升高。上述结果表明Smyd2通过降低IRF3的磷酸化水平从而负向调控病毒诱发的天然免疫反应过程而达到逃逸免疫得作用，其详细的调控机制需要进一步阐明，该课题将从负向调控以及蛋白甲基

Identifying the key molecules responsible for the efficient initiation of antiviral innate response and how the viruses can feedback inhibit the innate response for their immune escape is the key issue to be addressed in the field of molecule immunology. Transcriptional factor IRF3 plays critical role in induction of type interferons (IFNs) transcription to eliminate virus infection. There are reports about the activation and deactivation of IRF3, however, negative regulation of IRF3 activation process is not fully clarified. In this project, we screened the differentially expressed genes in mouse peritoneal macrophages with or without VSV infection by cDNA microarray. We found that, Smyd2, one member of SMYD (SET and MYND domain) family, was significantly downregulated in macrophages upon RNA virus infection. Also, knock-down of Smyd2 significantly increased typeⅠinterferons in macrophages. We further prepared Smyd2-/- mice, and confirmed typeⅠinterferons substantially increased in the serum and organs, which led to decreased virus load and increased survival ratio. We further found that phosphorylation of IRF3 significantly increased in Smyd2-deficient macrophages infected with VSV. Therefore, our results indicate that Smyd2 negatively regulate innate immune response by reduction of phosphorylation of IRF3. Therefore, the primary aim of this application is to investigate the molecular mechanisms involved this process from a view of epigenetic enzyme, trying to figure out the epigenetic regulation of IRF3-initiated antiviral innate immune response. This project will shed new light on the regulations of IRF3 activation, which might provide theoretical support and new target for control of virus infection.