Our proposal is focused on defining the molecular mechanisms by which hepatitis C virus (HCV) triggers inflammasome activation and signaling crosstalk from interleukin (IL)-1? 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.
Hepatitis C virus (HCV) is a major public health problem causing liver disease. Our studies will define the molecular basis of hepatic inflammation and innate immune activation in the outcome of HCV infection, immunity, and liver disease, and will determine the application for antiviral therapy mitigate these processes toward disease resolution.
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