Mechanisms of hepatic innate immune activation by HCV

我们的建议集中在定义丙型肝炎病毒(丙型肝炎病毒) 触发炎症小体激活和白介素1β的信号串扰以驱动肝脏 炎症、先天免疫激活，以及感染和免疫的治疗结果。丙型肝炎病毒 是世界范围内肝脏疾病的主要原因，其中疾病的标志是肝脏 炎症/慢性肝炎，最终损害肝功能。然而，分子 丙型肝炎病毒触发肝脏炎症传递免疫激活和 疾病是未知的，新的直接作用抗病毒(DAA)疗法的结果也不是 定义了这些流程。我们的研究揭示了肝脏巨噬细胞或“库普弗”的中心作用 通过激活NLRP3应答丙型肝炎病毒引发肝脏炎症的细胞 炎症体，并表明IL-1受体信号传递新的细胞因子串扰 促进先天免疫/炎症循环，推动肝脏先天免疫激活 强调肝脏疾病。重要的是，我们的初步研究表明， 在丙型肝炎患者中，通过DAA治疗的丙型肝炎病毒载量可以消除这一回路，从而可能解决 先天免疫激活和炎症信号。我们的研究设计包括两个目标： 丙型肝炎病毒激活肝巨噬细胞NLRP3炎症体的假说 通过病毒粒子推动肝脏炎症、先天免疫激活和慢性肝炎- 诱导的炎症体-细胞因子循环，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.