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.