Innate immunity and interferon signaling in viral hepatitis

Hepatitis C virus (HCV) infections become chronic in the majority of infected individuals, and chronic hepatitis C (CHC) can lead to cirrhosis and hepatocellular carcinoma. The innate immune system is central to host-virus interactions during the entire natural course of the disease (Heim MH, 2013). The HCV NS3/4A protease efficiently cleaves and inactivates two important signaling molecules in the sensory pathways that react to HCV pathogen associated molecular patterns (PAMPs) to induce interferons (IFNs), i.e. mitochondrial anti-viral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). Despite this viral escape mechanism, the innate immune system strongly reacts to HCV within the first days after infection. The sensory pathways, the type(s) of IFNs involved and the cellular source of IFNs are largely unknown. After 4 to 8 weeks, HCV specific T cells are recruited to the liver. IFN-γ stimulated genes get strongly expressed in the liver (Dill MT et al, 2012). In about 30% of patients the virus is eliminated during the acute phase of the infection by T cell mediated anti-viral mechanisms. In the remaining 70% of patients, HCV persists for decades. During this phase, T cell derived IFN-γ cannot be detected any more in liver biopsies. Instead, in about half of the patients, hundreds of type I or III IFN stimulated genes become again strongly expressed (Sarasin-Filipowicz M et al, 2008). However, this innate immune reaction is ineffective against HCV. Moreover, patients with constitutive IFN stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (pegIFN-α) and ribavirin (Sarasin-Filipowicz M et al, 2009)(Makowska Z et al, 2011)(Dill MT et al, 2011). The viral escape mechanisms that protect HCV from IFN mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cells with refractory IFN signal transduction pathways or to cell compartments that are not accessible to anti-viral IFN stimulated effector systems. Recently, genetic variations near the IL28B (IFN-λ3) were found to be strongly associated to spontaneous clearance of HCV and to response to treatment with pegIFN-α and ribavirin (Rauch et al, 2010). The finding supports a central role of the innate immune in host-viral interactions (Makowska M and Heim MH, 2012). The signaling pathways that link genetic variants of IL28B with immune answers to HCV remain to be elucidated.

Figures - Click to Enlarge