The host’s ability to respond to invasive pathogens depends on the activation of the innate immune system that coordinates adaptive immune responses to remove pathogens [16]. About HCV, one of the strategies used detects the presence of the virus by hepatocytes and innate immune cells is the triggering activation of TLR3, 7, 8, and 9 which are specific in HCV nucleic acids recognition. TLR3 bonded by dsRNA while TLR7/8 is recognizing ssRNA [17].
Upon engagement, these receptors initiating a cascade of events that results in transcription factor activation and induction of IFN-I and inflammatory cytokines leading to antiviral state acquisition [18]. It has been suggested that HCV uses several strategies to efficiently evade the IFN-I response through interfering with PRRs signaling cascade intermediate either by blocking TLR3-mediated pathway by using serine protease NS3/4A to cleave the key adaptor of TLR3 [19], TRIF [20], or by induction of miR-21 that has been reported to suppress the TLR7-mediated pathway upon suppression of MyD88 and IRAK1 expression [2, 12, 21,22,23].
However, most of these reports have been developed on in vitro transfected cell cultures or animal experimental systems. Here, the objective of the presented study was to evaluate TLR3 and TLR7 expression in patients chronically infected with hepatitis C virus infection and its association with IFN-α production. Our results indicated that the expression levels of TLR3, TLR7, and IFN-α were significantly downregulated in non-treated chronic HCV patients compared to both treated HCV patients and control subjects. On the other hand, treated HCV patients showed non-significant downregulation of the same three sensing receptors (TLR3, TLR7, and IFN-α) compared to the control group. The expression levels of IFN-α were positively correlated with the levels of both TLR3 and TLR7.
Moreover, this downregulation in chronic HCV infection, could be one of the mechanisms used by HCV to interfere with an early innate immune response through impairment of the IFNs mediated antiviral mechanisms that may therefore lead to impaired T cell activation, in agreements with previous studies that have reported in mice showing lacking MyD88 as a result of TLR7 signal disturbance [24] that is responsible for the persistent replication and eventually promote disease progression and establishment, a chronic infection in 70–80% of infected patients [19, 25].
Several studies have examined the nature of the relationship between HCV infection and the gene expression rate of TLR 3, 7, 8, and 9. Our findings were consistent with other studies reported that the expression levels of TLR3 and TLR7 were downregulated in patients with chronic HCV infection when compared with healthy subjects [26, 27]. Another study showed the decrease of TLR3 expression in the presence of HCV infection via NS4B-induced downregulating TRIF protein level also supported our findings [28]. Previous study examined a potential association between single-nucleotide polymorphisms (SNPs) in the TLR3, TLR9 genes, and HCV infection among Egyptian patients and showed its downregulation [29]. The presented study was also in agreement with reports that showed the expression levels TLR7 were significantly lowered in patients with chronic HCV and HCC compared to patients who naturally cleared their infection and controls [30].
However, our findings are contrary with another study that found HCV infection could lead to increased expression level of TLR7 mRNA in peripheral blood cells of HCV-infected samples [31]. However, this inconsistency can be due to the difference in patient’s selection, methodological approaches, clinical stage, the genetic background of the population, and HCV genotypes. In agreement with other previous studies, the correlation among TLR3, TLR7, IFN-α, and all biochemical parameters findings (ALT, AST, WBCs, HB, PLT) in the non-treated chronic HCV patients were non-significant [12]. We and other studies confirmed that the expression levels of TLR3 and TLR7 were strongly correlated with the expression level of IFN-α [27].
As a key component of innate immunity, the IFN system forms are the first line of defense against several pathogens to remove incoming infection and direct a subsequent adaptive response. From this standpoint, HCV infection leads to reduction in expression of TLRs (TLR3 and TLR7) on innate immune cells and hepatocytes with subsequent disruption of the process of IFN-α production which may be considered as an evolving strategy that allows the virus to exploit the immune system of its host and ensure survival and replication. So, the presented were designed to highlight a deeper understanding of the anti-immune mechanisms of the HCV that targets TLR signaling pathways, especially in a chronic stage, where HCV key protein players and regulators can be identified as useful targets. Also, the weaknesses of the host defenses can be detected and HCV immune response is more accurately controlled. Accordingly, several TLR ligands have been studied as a synthetic activator of certain TLRs. For instance, application of the TLR7 agonist ANA773 isatoribine has been shown to markedly enhance viral clearance by the immune system, as monitored by dose-dependent dynamics of immunological biomarkers [24]. In addition, synthetic dsRNA (poly I:C) TLR3 antagonists, such as dsRNA mimic polyinosinic: polycytidylic acid (poly I:C) induced stimulation and reactivation of DCs that could induce the immune responses against HCV infection [32].