Mechanisms of hepatic innate immune activation by HCV

我们的建议集中在定义丙型肝炎病毒（HCV） 触发炎性小体激活和白细胞介素（IL）-1β的信号串扰， 炎症、先天免疫激活以及感染和免疫的治疗结果。HCV 是世界范围内肝病的主要原因，其中疾病的特征是肝硬化。 炎症/慢性肝炎，最终损害肝功能。然而，分子 HCV触发肝脏炎症以赋予免疫激活的机制， 疾病是未知的，也没有新的直接作用的抗病毒（DAA）治疗的结果， 这些过程被定义。我们的研究揭示了肝巨噬细胞或“枯否细胞”的核心作用， 细胞”应答HCV，通过激活NLRP 3触发肝脏炎症 炎性小体，并显示IL-1受体信号传递赋予新的细胞因子串扰， 促进驱动肝脏先天免疫激活的先天免疫/炎症回路 强调肝脏疾病。重要的是，我们的初步研究表明， 通过DAA治疗HCV患者的HCV载量可以废除该回路，以可能解决 先天免疫激活和炎症信号传导。我们的研究设计包括两个目的， 研究HCV激活肝巨噬细胞中的NLRP 3炎性小体的假设， 通过病毒体驱动肝脏炎症、先天免疫激活和慢性肝炎， 诱导的炎性体-细胞因子环，其是免疫激活和肝脏疾病的基础。

Our proposal is focused on defining the molecular mechanisms by which hepatitis C virus (HCV) triggers inflammasome activation and signaling crosstalk from interleukin (IL)-1β to drive hepatic inflammation, innate immune activation, and therapeutic outcome of infection and immunity. HCV is a major cause of liver disease worldwide, wherein disease is marked by hepatic inflammation/chronic hepatitis that eventually compromises liver function. However, the molecular mechanisms by which HCV triggers hepatic inflammation to impart immune activation and disease are not known nor has the outcome of the new direct acting antiviral (DAA) therapy on these processes defined. Our studies reveal a central role for hepatic macrophages or “Kupffer cells” in responding to HCV to trigger hepatic inflammation through activation of the NLRP3 inflammasome, and show that IL-1 receptor signaling imparts novel cytokine crosstalk that promotes an innate immune/inflammatory circuit driving hepatic innate immune activation underscoring liver disease. Importantly, our preliminary studies suggest that the acute drop of HCV load by DAA therapy in HCV patients can abrogate this circuit for possible resolution of innate immune activation and inflammatory signaling. Our study design comprises two Aims to investigate the hypothesis that HCV activation of the NLRP3 inflammasome in liver macrophages drives hepatic inflammation, innate immune activation, and chronic hepatitis through a virion- induced inflammasome-cytokine loop that underlies immune activation and liver disease.