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MDA5 plays a critical role in interferon response during hepatitis C virus infection. BACKGROUND & AIMS: Hepatitis C virus (HCV) is a human pathogen that can evade host immunity to cause persistent infection, leading to liver cirrhosis and hepatocellular carcinoma. The transfected 3'UTR of HCV genomic RNA can be recognized by host protein RIG-I to activate interferon production in hepatocytes. However, it is difficult to demonstrate the RIG-I mediated sensing of HCV genomic RNA in the context of HCV infection because HCV-encoded NS3-4A protease can inactivate MAVS, a critical adaptor protein in interferon signaling. Our aim was to identify the viral sensor that triggers interferon response in hepatocytes during HCV infection. METHODS: We generated a hepatic cell line that stably expressed mutant MAVS resistant to the NS3-4A cleavage. This cell line allowed us to investigate the interferon signaling pathway in the context of HCV infection. By using the knockdown and knockout technology together with biochemical approaches, we were able to identify the actual viral sensor in hepatocytes during HCV infection. RESULTS: We showed that HCV infection induced robust interferon response in the cells expressing MAVS resistant to the NS3-4A cleavage. Unexpectedly, the interaction between HCV's 3'UTR and RIG-I seemed to play a minor role in this activation, while another helicase MDA5 played a more important role in sensing HCV infection to trigger interferon response. CONCLUSIONS: Our data demonstrate that MDA5 recognizes HCV to initiate host innate immune response during HCV infection. This study provides insight into how host senses HCV to initiate innate immunity during HCV infection.