Role of the Innate Immune System During HCV Infection

The innate immune response represents the first line of defense against pathogens and is maintained by complement, natural killer (NK), natural killer T cells (NKT) cells, and macrophages. It is widely accepted that this arm of the immune system is effective in removing most pathogens that infect the body. The innate immune response also plays an important role in activating and amplifying the adaptive immune system (Trobonjaca et al., 2001; Chan et al., 2006). Viruses produce viral pathogen-associated molecular patterns (PAMPs) that are able to initiate a cascade of events leading to innate intracellular immunity. In the case of HCV, the double-stranded RNA initiates two major pathways of host defense by binding to Toll-like receptor 3 and retinoic-acid inducible gene I (RIG-1) [reviewed in (Gale & Foy, 2005)].

Several reports in both chimpanzee and humans indicate that the virus activates the innate immune response before and during acute infection by inducing secretion of endogenous type I interferon (IFN-a and -ß) and by activating NK cells. Analysis of gene microarray experiments from experimentally infected chimpanzee liver biopsies has revealed the induction of a broad range of IFN-a inducible genes (ISGs) (Bigger et al., 2001, 2004; Su et al., 2002), including some involved in the regulation of NK cells, confirming the induction of IFNs during the course of acute infection. Expression of IFN has three major roles: (1) to induce ISGs that have an antiviral action; (2) to induce the maturation of immune effector cells; and (3) to create a pro-inflammatory environment following upregulation of cytokine expression by liver cells. An ongoing type I IFN response appears to be important to limit viral replication and spread until the adaptive immune response plays its role. This is suggested by in vitro studies demonstrating that HCV replicons are extremely sensitive to IFN-a (Blight et al., 2000; Guo et al., 2001; Lanford et al., 2003), by the high rate of viral clearance when IFN-a is administered during the acute phase of infection (Jaeckel et al., 2001; Santantonio et al. , 2005) (reduction to a 10% chronicity rate) and by the effectiveness of IFN-a and ribavirin treatment in chronically infected individuals (Manns et al., 2001). However, it seems that the natural induction of type I IFNs alone is unable to control viral replication (Thimme et al., 2001, 2002; Su et al., 2002). It is therefore likely that the virus inhibits the downstream antiviral effects of IFN. Various HCV proteins have been shown to inhibit IFN-related genes in vitro. The HCV serine protease NS3-NS4A blocks induction of type I IFNs by functioning as an antagonist of IFN regulatory factor-3 (IRF-3) (Foy et al., 2005; Li et al., 2005), while E2 and NS5A proteins interact in vitro and can repress the double-stranded RNA-dependent protein kinase (PKR) (Gale et al., 1997, 1998; Pavio et al., 2002). HCV has also been shown to affect the Jak-Stat pathway (Katze et al., 2002; Blindenbacher et al., 2003; Foy et al., 2003). While the role of the innate immunity in HCV infection outcome is detailed in another chapter, it should be noted that activation of the innate immune response promulgates a cascade that is critical to the initiation and maturation of the adaptive immune response. Thus, defects in the innate immune response induced by the hepatitis C virus might have crucial downstream effects on the development of adaptive immune responses capable of mediating viral clearance.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment