Introduction
Immune response variations 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 get into the cell through receptor-mediated endocytosis. The structure of HCV with different parts are recognized by different TLRs. The core and non-structural (NS) proteins are vital 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 critical for its antiviral immune actions, as it stimulates non-parenchymal liver to regulate HCV replication through the synthesis of interferon (IFN)-β [4, 5]. In chronic HCV infections, TLR3 mRNA is significantly increased in monocytes [6]. An IFN-responsive element has been identified in the TLR3 gene promoter region and, so, it appears likely that expression TLR3 is responsive to IFN treatment in HCV infection [7]. Myeloid dendritic cells (mDCs) have ordinary operative TLR3 and are capable of producing interleukin (IL)-12, IL-6, IL-10, IFN-γ, and tumour necrosis factor (TNF)-α with TLR3 stimulation regardless of HCV infection [8].
HCV viral proteins activate TLR signalling, which plays a significant role in viral immune clearance. However, HCV can at the same time evade immune clearance by targeting and ruining TLR signal transduction via numerous mechanisms. First, HCV intervenes 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 prevents IRF3 and NFκB activation by downgrading the amount of TRIF in serum and by producing cleavage products with dominant-negative action [4, 9]. NS3/4A, also, interacts directly with TBK1 to reduce the interaction between TBK1 and IRF3 and, so 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 the expression of TLR9 through the transcription factor (Elk-1), which is an essential signal integration point between T-Cell Receptor (TCR) and CD28 in T helper 1 (Th1) cell activation [12]. HCV, also, impedes the production of IFN-α and IFN-β through TLR9 and decreases human leukocyte antigen DR (HLA-DR) expression by pDCs, linked to diminished activation of naïve T cells [13]. TLR9 signalling in mDCs is unchanged [8, 13]. Consequently, it is clear that compartmentalization of the outcomes on TLR function is a crucial strategy by which HCV can escape immune surviellance yet can lead to chronic inflammatory hepatic injury and 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.