FMDV VLP通过甘露糖受体启动肥大细胞应答的表观遗传学调控机制研究

口蹄疫（FMD）是由口蹄疫病毒（FMDV）感染偶蹄动物所引起的一种急性传染病，可引起免疫抑制，严重影响畜牧业与食品安全。FMDV病毒样颗粒（VLP）是在体内不能复制、没有致病性的粒子，与亲本病毒有相似的结构特征和抗原特性。前一基金项目研究结果表明，甘露糖受体（MR）识别VLP后所激活的转录因子可能与肥大细胞（MCs）染色质DNA的多个基因位点相结合，从而启动多种细胞因子的表达；MCs通过MR启动抗FMDV的应答可能受到了表观遗传学的调控。因此，本研究阻断MCs的MR，再负载VLP，利用RNA-seq分析转录谱，利用ATAC-seq分析可接近的染色质DNA区域，利用ChIP-seq分析转录因子结合的DNA序列，并用组蛋白去乙酰化酶和DNA甲基化的抑制剂处理肥大细胞，以阐释FMDV VLP通过MR启动肥大细胞应答的表观遗传学调控机制，为研制FMD新型疫苗及筛选药物作用新靶点探索新途径与新方法。

Foot-and-mouth disease (FMD), caused by foot-and-mouth disease virus (FMDV), is an acute infectious disease of cloven-hoofed animals, which can cause immunosuppression, threatening animal agriculture and food safety worldwide. FMDV virus-like particles (VLP) are non-replicatble, non-pathogenic particles in vivo. They have similar structural characteristics and antigenicity with the parental viruses. The results of the previous project founded by Natural Science Foundation of China indicated that the transcription factors activated by mannose receptor (MR) recognition of VLP may bind to multiple genes loci of chromatin DNA of mast cells (MCs), thus triggering the expression of multiple cytokines. The response of MCs to FMDV initiated by MR may be regulated by epigenetics. Therefore, mannose receptors expressed on mast cells are blocked with corresponding technique. These mast cells are pulsed with FMDV VLP, then the transcriptional profile of mast cells is analyzed by RNA-seq and the accessible chromatin DNA sequences are assessed by ATAC-seq, and then DNA sequences bound by key transcription factors are identified by ChIP-seq. Mast cells were treated with inhibitors of histone deacetylase and DNA methylation, respectively. Our aim is to elucidate the epigenetic regulation mechanism of FMDV VLP initiating mast cells response via MR. It is believed that pending results of our winning proposal will pave the way for novel vaccine development and screening new therapeutic targets.