Interaction of Hepatitis C virus proteins with pattern recognition receptors

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.

Hepatitis B and C virus-induced hepatitis: Apoptosis, autophagy, and unfolded protein response

“…In addition, siRNA-targeting ATGs, that inhibit autophagy, abrogates HCV replication [69] . Moreover, HCV infection activates various pattern recognition [70] , being able to trigger autophagy [71] .…”

Distinct Toll-like Receptor 3 and 7 Expression in Peripheral Blood Mononuclear Cells from Patients with Chronic Hepatitis C Infection

“…It is suggested that HCV interferes with TLR signaling pathway via interaction with their signaling intermediates (16, 18) or altering their expression levels (10, 12). The data presented in this study indicated that HCV downregulats the expression of TLR3 in PBMC of patients with HCV-infected chronic liver disease.…”

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

“…TRIF overexpression mice are less susceptible to encephalomyocarditis virus (EMCV) infection, have a significantly lower viral load in the heart . Non structural 3/4 A protein of hepatitis C virus (HCV) disrupts TLR3 and RIG-I signaling pathways by cleaving TRIF and IPS-1 (IFN-b promoter stimulator 1), thus halting the defense against HCV (Imran et al, 2012).…”