胆汁酸受体FXR调控干扰素转录影响肝脏病毒感染的功能和机制研究

Activation of Type I interferon signaling pathway is the main way for suppressing viral replication in host cells. However, redundant interferon expression causes cellular apoptosis and tissue damage. The host cells have to accurately control the transcription of interferon in order to balance the anti-viral effect and tissue protection. Up till now, the nuclear regulation of interferon signaling is not clear. By screening the function of nuclear receptors in interferon transcription, we found that FXR, which is the nuclear receptor of bile acid, can significantly inhibit the IFN-β transcription, and affect the viral replication and apoptosis. The transcriptional complex of IRF3 may play important roles in FXR-regulated interferon inhibition. Since FXR expresses mainly in hepatocytes and intestinal cells, we will further delineate the function of bile acid responded by FXR in viral infection of hepatocytes. To explore the role of FXR-suppressed interferon transcription in viral infection of liver, immunoprecipitation/CHIP/EMSA will be used to investigate the molecular mechanism of FXR-regulated interferon transcription. The synergistic administration of FXR inhibitor and apoptosis inhibitor is applied to explore the feasibility of enhanced interferon expression to inhibit viral replication and improve tissue protection simultaneously. Our research will not only enrich novel mechanism of innate immunity regulation of viral immunity, but also provide new strategy and target for eliminating hepatitis virus and developing new drug of anti-viral infection.

宿主细胞通过激活I型干扰素信号通路来抑制病毒复制，但过量的干扰素表达易致细胞凋亡与组织损伤，通过多重途径精确调控干扰素转录是宿主细胞平衡抗病毒效应与组织保护的手段，然而干扰素通路在细胞核内的调控机制尚不清楚。通过筛选细胞核受体在干扰素转录中的功能，我们发现胆汁酸受体FXR显著抑制IFN-β的转录，并进而影响病毒复制和细胞凋亡，IRF3转录复合体形成可能在其中扮演重要角色。FXR主要表达在肝肠细胞中，我们拟在此基础上进一步证实FXR感应的胆汁酸信号在肝细胞病毒感染中的功能；使用免疫共沉淀、CHIP、EMSA等明确FXR发挥功能的分子机制，阐明FXR抑制干扰素转录在肝炎病毒感染中的作用，并通过FXR抑制剂与凋亡抑制剂联用，探究增强干扰素表达抑制病毒复制的同时减少组织损伤的可行性。本研究有望充实现有天然免疫信号通路调节的理论体系，且为研发新抗病毒药物和清除肝炎病毒提供新思路和靶点。

本项目总体执行顺利，项目计划的各年度研究内容正常执行。我们的研究结果发现，FXR通过结合细胞核内的干扰素转录因子IRF3，从而抑制IRF3结合到目的基因启动子，最终抑制干扰素基因的表达。此外，我们还发现胆汁酸盐CDCA能够激活胆汁酸受体TGR5增强干扰素信号通路活化，也激活FXR抑制干扰素基因的转录。使用CDCA联合FXR抑制剂GUGG处理细胞，能够显著增强宿主细胞的抗病毒能力。在项目执行期间，我们不仅阐释了胆汁酸受体FXR调节干扰素信号通路和病毒感染的分子机制，并为解析胆汁酸盐CDCA和DCA复杂的抗病毒功能提供了证据。本项目如期完成了研究目标，相关数据已经整理并撰写文章，研究论文在投稿过程中。此外，依托本项目的相关研究结果，项目主持人在Autophagy、Molecular Immunology等SCI杂志发表论文2篇。