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Abstract
Hepatitis C virus (HCV) is an important human pathogen that causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. This positive stranded RNA virus is extremely efficient in establishing persistent infection by escaping immune detection or hindering the host immune responses. Recent studies have discovered two important signaling pathways that activate the host innate immunity against viral infection. One of these pathways utilizes members of Toll-like receptor (TLR) family and the other uses the RNA helicase retinoic acid inducible gene I (RIG-I) as the receptors for intracellular viral double stranded RNA (dsRNA), and activation of transcription factors. In this review article, we summarize the interaction of HCV proteins with various host receptors/sensors through one of these two pathways or both, and how they exploit these interactions to escape from host defense mechanisms. For this purpose, we searched data from Pubmed and Google Scholar. We found that three HCV proteins; Core (C), non structural 3/4 A (NS3/4A) and non structural 5A (NS5A) have direct interactions with these two pathways. Core protein only in the monomeric form stimulates TLR2 pathway assisting the virus to evade from the innate immune system. NS3/4A disrupts TLR3 and RIG-1 signaling pathways by cleaving Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF) and Cardif, the two important adapter proteins of these signaling cascades respectively, thus halting the defense against HCV. NS5A downmodulates the expressions of NKG2D on natural killer cells (NK cells) via TLR4 pathway and impairs the functional ability of these cells. TLRs and RIG-1 pathways have a central role in innate immunity and despite their opposing natures to HCV proteins, when exploited together, HCV as an ever developing virus against host immunity is able to accumulate these mechanisms for near unbeatable survival.
Highlights
HCV infection is a major cause of acute hepatitis and chronic liver disease
NS5A interacts with TLR4 on monocytes and leads to the secretion of IL-10 through p38 and PI3 kinase pathways and concurrently suppresses the production of proinflammatory IL-12
HCV core protein interacts with TLR2 & TLR4 and stimulates various pro-inflammatory and antiinflammatory cytokines
Summary
HCV infection is a major cause of acute hepatitis and chronic liver disease. HCV was first identified in 1989 [1]. The initial step for the stimulation of cytokine response in RNA virus infection is cellular activation of dsRNA receptor systems, Toll-like receptor 3 (TLR3) [51,52] and retinoic acid inducible gene-I (RIG-I) [53] These two pathways lead to the activation of IκB kinase (IKK) α/β/γ complex and IKK-like kinases e.g. IKKE and TANK binding kinase 1 (TBK1) [53,54,55,56,57]; which mediate the activation and nuclear translocation of NFκB and interferon regulatory factor 3 (IRF3) [58,59]. The proteolytic processing of components of both TLR3 and RIG-I pathways, lead to the abrogation of the cascade that activates IRF3 and NFκB This in turn fails to induce genes that express IFN-α and -β, and additional cytokines that are crucial for stimulating other arms of the immune system. The functional consequences of this NKG2D reduction are associated with impaired production of IFNγ and CD107a degranulation by NK cells [82]
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