Activation of cGAS-STING signaling pathway during HCV infection

Abstract

Hepatitis C virus (HCV) is a major global health issue, infecting over 170 million people worldwide and leading to severe liver diseases, including cirrhosis and hepatocellular carcinoma. The ability of HCV to persist and cause chronic infection is partly due to its evasion of the hosts innate immune responses, particularly those mediated by the RIG-I-MAVS pathway, which is critical for antiviral defense. Studies have shown the crucial role genome sensing of DNA viruses by cyclic GMP-AMP synthase (cGAS) followed cGAMP production and activation of downstream effector STING (stimulator of interferon genes) to induce IFN-{beta}, however it is not understood in RNA viruses specially in HCV infection. In this study, we explored first time the mechanism of the cGAS-STING pathway in the context of HCV infection, specifically using the JFH-1 strain of HCV (genotype 2a). We observed that cGAS expression is significantly upregulated during the early HCV infection, leading to the production of the second messenger cyclic GMP-AMP (cGAMP), which in turn activates STING. This activation results in the significant induction of type I interferon responses, particularly interferon-{beta} (IFN-{beta}), which is essential for mounting an effective antiviral response. Moreover, our results demonstrated the translocation of cGAS and STING with cellular organelles such as the endoplasmic reticulum (ER) and mitochondria. This suggests that the cGAS-STING pathway is intricately linked with other cellular signaling networks in detecting and responding to HCV infection. Furthermore, knockdown experiments targeting cGAS, STING and RIG-I revealed that these proteins play a crucial role in suppressing HCV replication, underscoring their potential as therapeutic targets. These findings provide valuable insights into the molecular mechanisms of the cGAS-STING pathway in mediating the innate immune response against HCV. Understanding this pathways role in the immune defense against HCV opens up new possibilities for therapeutic strategies aimed at enhancing the hosts antiviral immunity and potentially developing new treatments for chronic HCV infection.