ELF4相关抗病毒天然免疫信号通路研究

人类面临众多疾病威胁, 其中病毒感性传染病危害程度高、治疗难度大、对社会造成的影响广泛。 而疫苗对新发突发病毒传染病的防治作用很有限，亟待发展新型广谱抗病毒药物。抗病毒天然免疫研究为解决该世界难题开辟了新途径。天然免疫是机体抵御病原微生物的第一道防线，能对感染做出迅速应答，并诱导免疫基因来清除入侵者。初期工作中我们发现ELF4是一个新的天然免疫调节子，在抗病毒反应中发挥作用。在初期筛选过程中发现病毒感染后ELF4能够调节多个miRNA的表达，并鉴定出了miRNA的相关靶向蛋白HIPK2，以及ELF4相互作用蛋白HnrnpU。初步数据显示HIPK2和HnrnpU参与了ELF4相关抗病毒天然免疫反应。在本项目中，将重点研究：ELF4对于miRNA的调节机制，和miRNA的免疫调节和抗病毒功能；HIPK2抗病毒功能，和对I型干扰素的的调节机制；ELF4相关信号通路的调节机制和HnrnpU的功能。

The world faces a series of health threats, including viral infection diseases that are difficult to treat，and can cause great harm to public health and Social stability. By far vaccine is the most effective way of tackling serious infectious diseases, but its role in preventing new outbreaks of viral infection is very limited, so it is urgent to develop new broad-spectrum antiviral drug. The innate antiviral immunity opens up a new way to solve the difficult problem in the world. Innate immunity serves as the first line of host defense. The receptors of innate immunity can recognize the invading pathogens and initiate the down stream signaling to induce a panel of cytokines and immune genes to kill the invaders. Our preliminary results have shown ELF4 is a new regulator of innate immune signaling that is critical for antiviral immune responses. We identify 25 microRNAs that is regulated by ELF4 in response to viral infection. One of them is miR-221 that can down regulate the expression of HIPK2. HIPK2 is known playing roles in tumoregenesis and necrosis. We here found HIPK2 can induce type I interferon. We also identify an ELF4 associate protein HnrnpU through co-immunoprecipitation screening. Therefore, in this project, we are going to study: (1) The mechanism how were the miRNA regulated by ELF4, the role of the miRNA in antiviral immunity; (2) The role of HIPK2 in type I regulation and antiviral immune responses; (3) Signal transduction mechanism of ELF4 related innate immunity and role of HnrnpU in this process.