Innate Immune Responses to Hepatitis C Virus Infections
Research Project
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01.04.2013
- 31.03.2016
Chronic hepatitis C (CHC) is a major cause of chronic liver disease. An important and striking feature of hepatitis C virus (HCV) is its tendency toward chronicity. In > 70% of infected individuals, HCV establishes a persistent infection over decades that may lead to cirrhosis and hepatocellular carcinoma. This high rate of persistence is linked to an ability of HCV to evade and antagonize the immune response of the host. Type I interferons (IFNs) are crucial and potent components of the early host response against virus infection and recombinant pegylated IFNα (pegIFNα) in combination with ribavirin is the current standard therapy for CHC. About half of the patients can be cured. In the current research grant application, we plan to address several key points of the innate immune response to hepatitis C virus infection. 1. Analysis of liver biopsies of HCV infected patients with a newly developed fluorescence in situ hybridization method (FISH). We will use a newly developed FISH method to visualize and quantify HCV RNA and mRNAs of IFNs and IFN stimulated genes in liver biopsies. 2. IFNα induced signaling in the human liver. The pharmacodynamic effects of pegylated IFNα will be studied in liver biopsies obtained at different time points during the week after the first injection of pegylated IFNα in patients with CHC . 3. The role of IFNλ in establishing and maintaining IFN stimulated gene expression in the liver of HCV infected patients. We plan to systematically study IFNλ and IFNλ receptor expression in liver biopsies of patients with chronic hepatitis C (and controls) and correlate the status of the IFNλ system with hepatic IFN stimulated gene expression. We will investigate the molecular mechanisms that links IL28B genotype with IFN stimulated gene expression and with non-response to pegIFN-α/ribavirin combination therapies. 4. Functional characterization of IFNα induced long non-coding RNAs (lncRNAs) We have identified hundreds of lncRNAs that are induced by IFNα. We plan to study if some of them have a role in negative regulation of genes by IFNα.
