MMP3入核激活NFkB：MMP3抗登革病毒感染的新机制？

研究宿主抗登革病毒感染的机制对了解登革热的发病过程具有重要意义。在研究宿主JAK-STAT信号通路及其下游效应分子抗登革病毒感染的过程中，我们发现基质金属蛋白酶3- - MMP3在登革病毒感染的细胞中高表达，抑制MMP3，病毒感染水平显著上升，而细胞抗病毒相关细胞因子的表达普遍下降。进一步发现，MMP3在病毒感染过程中能进入到细胞核内，并直接影响转录因子NFκB的活性。本项目将在前期工作基础上，采用免疫荧光、免疫沉淀、报告基因实验、细胞病毒感染、定量PCR等多种技术手段，深入研究MMP3在抗登革病毒感染中的分子机制，了解其在进入细胞核、影响NFκB转录活性、放大细胞抗病毒效应过程中的具体作用。并在此基础上探讨MMP3在不同登革感染者血细胞中表达水平及其与疾病发展的关系。本项目将首次揭示MMP3这个古老的分子进入细胞核发挥抗病毒效应的全新功能，为MMP家族参与免疫调控反应提供新的证据。

Dengue virus （DENV）infection is still a world-wide health threaten. Study of the host anti-viral mechanism is important for us to understand the process of Dengue fever disease. Our current work focused on the role of JAK-STAT pathway and its downstream factors during DENV infection in macrophage model. Matrix metalloproteinase 3(MMP3) was found to be induced during DENV infection. Silencing MMP3 in macrophage, the DENV infection level significantly increased, while the anti-viral cytokine production impaired. Further experiments shown that MMP3 was translocated into cell nucleus upon DENV infection and influenced the activity of transcriptional factor NFκB. Based on these data, we will further characterize the detail function of MMP3 during DENV infection. Immunofluorescence, immunoprecipitation, reporter assay, cell-based viral infection and quantitative PCR will be used to study the mechanisms of the nuclear translocation of MMP3 and the relationships between MMP3 and NFκB during DENV infection. We will further investigate the expression of MMP3 in blood cells from DENV infected patients, and the link between MMP3 and Dengue fever diseases. This will be the first time to show the novel anti-viral function of MMP3 in cell nucleus, and provide new evidence for the role of MMPs in immune modulation. This work will also contribute to the development of new anti-viral drugs based on MMPs.