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.