Hepatitis C virus (HCV) is an emerging infectious disease. Patients exposed to this virus frequently fail to clear this viral infection and become chronic carriers. Chronic infection by this virus can lead to severe liver diseases including cirrhosis and hepatocellular carinoma. How HCV evades host immunity to establish chronic infection, however, remains largely unclear. Studies in recent years indicate that HCV can suppress intracellular antiviral responses. The goal of this research project is to further investigate how HCV interacts with its host cells to evade intracellular innate immunity. RIG-I is an important pattern recognition receptor (PRR) in cells and its activation can lead to a cascade of antiviral responses. Recent studies indicate that HCV can disrupt RIG-I signaling. Thus, the goal of specific aim 1 of this project is to further investigate the interactions between HCV and RIG-I signaling. PKR is a double-stranded RNA dependent protein kinase. It is another important PRR in cells. Its activation will result in the inactivation of the translation initiation factor elF2alpha for the suppression of cellular and viral protein synsthesis. Our recent studies indicate that HCV could induce the phophorylation of elF2alpha, which does not appear to suppress HCV replication. Thus, the goal of specific aim 2 is to further investigate the role of PKR and elF2alpha in anti-HCV response. Autophagy is an important arm of innate immunity. It can remove intracellular pathogens including viruses and is also critical for delivering cytosolic viral RNA to endosomes for the activation of toll-like receptor 7 (TLR7). Our recent studies indicated that HCV could suppress the fusion between autophagosomes and endosomes/lysosomes. This effect of HCV on host cells may be important for preventing the activation of TLR7. The goal of specific aim 3 is to further investigate how HCV perturbs the autophagic pathway and to study the possible effect of this perturbation on the activation of TLR7. The research of this project will lead to a better understanding of the interaction between HCV and its host cells. Thus, it will contribute positively to this Program to enhance the understanding of how host cells control viral replication and how viruses suppress intracellular antiviral defenses.
HCV is an important human pathogen. Our proposed research will lead to a better understanding of the life cycle of HCV. This understanding will be important for the improvement of treatments for HCV patients.
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