Introduction
Variations in immune responses may help define successful resistance to Hepatitis C virus (HCV) infection particularly among seronegative healthcare workers, reviewed elsewhere [1]. Toll-like receptors (TLR)-3 are innate detectors of dsRNA of viruses while TLR9 recognizes bacterial and viral unmethylated CpG motifs. HCV virions bind to the cell surface and enter the cell via receptor-mediated endocytosis. The structure of HCV with different parts are recognized by different TLRs. The core and non-structural (NS) proteins are important sequences recognized by pattern recognition receptors (PRRs), including TLRs. They are, also, important inhibitors of TLR signalling [2, 3]. HCV core and NS proteins are important pathogen-associated molecular patterns (PAMPs) for TLR2, TLR3, TLR4, TLR7, 8, and 9. TLR3 is important for its antiviral immune effects, and TLR3 stimulated non-parenchymal liver cells are able to regulate HCV replication through production of interferon (IFN)-β [4, 5]. TLR3 mRNA is significantly increased in monocytes in chronic HCV infection [6]. An IFN-responsive element has been identified in the promotor region of the TLR3 gene, and it, therefore, seems likely that TLR3 expression is responsive to IFN treatment in HCV infection [7]. Myeloid dendritic cells (mDCs) have normal functioning TLR3 and can produce interleukin (IL)-12, IL-6, IL-10, IFN-γ, and tumour necrosis factor (TNF)-α with TLR3 stimulation despite HCV infection [8].
HCV viral proteins stimulate TLR signalling, which plays an important role in viral immune clearance. However, HCV can simultaneously evade immune clearance through specifically targeting and impairing TLR signalling through several mechanisms. First, HCV interferes with signalling via the TIR-domain-containing adapter-inducing IFNβ/TANK-binding kinase (TRIF)/ TBK)1- Interferon regulatory factor 3 (IRF3) pathway. The HCV NS3 protein induces degradation of TRIF, while the NS3/4A protein impedes IRF3 and NFκB activation by reducing the amount of TRIF in circulation and by generating cleavage products with dominant-negative activity [4, 9]. NS3/4A, also, interacts directly with TBK1 to reduce TBK1-IRF3 interaction and, therefore inhibit IRF3 activation [10]. HCV, also, interferes with the TLR-MyD88 (Myeloid differentiation primary response 88) pathway through NS5A interaction with MyD88 to prevent Interleukin-1 receptor associated kinase 1 (IRAK1) recruitment and cytokine production in response to ligands for TLR2, TLR4, TLR7, and TLR9 [11].
HCV has been shown to regulate TLR9 expression via transcription factor (Elk-1), which is an important signal integration point between T-Cell Receptor (TCR) and CD28 in T helper 1 (Th1) cell activation [12]. HCV also impairs TLR9-mediated IFN-α and IFN-β production and human leukocyte antigen DR (HLA-DR) expression by pDCs, associated with impaired activation of naïve T cells [13]. TLR9 signalling in mDCs is unaffected [8, 13]. It is, therefore, clear that compartmentalization of effects on TLR function is a key strategy by which HCV can evade immune clearance yet still lead to chronic inflammatory hepatic damage and liver fibrosis.
We previously showed that TLR3.rs3775290 “CC” genotype was associated with HCV chronicity, while TLR9 gene played no major role in HCV infection [14]. This study identified the role of TLR3.rs3775290 (c.1377C/T), TLR9.rs5743836 (-1237T→C) and TLR9.rs352140 (G2848A) single nucleotide polymorphisms (SNP) in predicting the outcome of HCV-specific cell-mediated immunity (CMI) among Egyptian healthcare workers (HCWs) and patients. We show that TLR9.rs5743836 SNP; but not TLR3.rs3775290 or TLR9.rs352140 genotypes; could predict the outcome of HCV-specific CMI responses among genotype-4-infected Egyptians.