Hou Zhaohua, Zhang Jian, Han Qiuju, Su Chenhe, Qu Jing, Xu Dongqing, Zhang Cai, Tian Zhigang
Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
Sci Rep. 2016 May 23;6:26150. doi: 10.1038/srep26150.
Previous studies showed that hepatitis B virus (HBV), as a latency invader, attenuated host anti-viral immune responses. miRNAs were shown to be involved in HBV infection and HBV-related diseases, however, the precise role of miRNAs in HBV-mediated immunosuppression remains unclear. Here, we observed that down-regulated RIG-I like receptors might be one critical mechanism of HBV-induced suppression of type I IFN transcription in both HBV(+) hepatoma cell lines and liver cancer tissues. Then, miR146a was demonstrated to negatively regulate the expression of RIG-I-like receptors by directly targeting both RIG-I and RIG-G. Further investigation showed that antagonizing miR146a by anti-sense inhibitors or sponge approach accelerated HBV clearance and reduced HBV load both in vitro and in a HBV-carrying mouse model. Therefore, our findings indicated that HBV-induced miR146a attenuates cell-intrinsic anti-viral innate immunity through targeting RIG-I and RIG-G, and silencing miR146a might be an effective target to reverse HBV-induced immune suppression.
先前的研究表明，乙肝病毒（HBV）作为一种潜伏性入侵者，会削弱宿主的抗病毒免疫反应。研究表明，微小RNA（miRNA）参与了HBV感染及HBV相关疾病，然而，miRNA在HBV介导的免疫抑制中的确切作用仍不清楚。在此，我们观察到，在HBV（+）肝癌细胞系和肝癌组织中，RIG-I样受体下调可能是HBV诱导I型干扰素转录受抑制的一个关键机制。随后，miR146a被证实可通过直接靶向RIG-I和RIG-G来负向调节RIG-I样受体的表达。进一步研究表明，在体外及携带HBV的小鼠模型中，用反义抑制剂或海绵法拮抗miR146a均可加速HBV清除并降低HBV载量。因此，我们的研究结果表明，HBV诱导的miR146a通过靶向RIG-I和RIG-G来削弱细胞内在的抗病毒天然免疫，而沉默miR146a可能是逆转HBV诱导的免疫抑制的一个有效靶点。
