Ikram Sghaier1, Leila Mouelhi2, Ezzedine Ghazoueni3, Etienne Brochot4, Wassim Y Almawi5, Besma Yacoubi-Loueslati5. 1. University of Tunis El Manar, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, 2092, Tunisia. Electronic address: sghaiere.ikram@gmail.com. 2. Charles Nicolle Hospital, Hepato-Gastro-Enterology Department, Tunis, Tunisia. 3. Military Hospital of Tunis, Laboratory of Immunology, Tunis, Tunisia. 4. Department of Virology, Amiens University Medical Centre, Amiens, France; Virology Research Unit, EA 4294, Jules Verne University of Picardie, Amiens, France. 5. University of Tunis El Manar, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, 2092, Tunisia.
Abstract
OBJECTIVES: TLRs are one of the most studied families of pathogen recognition receptors (PRRs) and play a pivotal role during HCV infection. The binding of ligands to TLRs on antigen presenting cells (APCs) leads to secretion of inflammatory cytokines, such as IL6, and induction of the acquired immunity response. Therefore, it has become necessarily to harness the TLRs properties' on therapeutically tools to enhance the HCV treatment response. Herein, we investigated the association between TLR3, TLR4 variants and nine IL-6 polymorphisms, and response to anti-viral treatment during HCV infection. METHODS: Study subjects comprised 120 patients infected with HCV-1b and treated with Peg-IFN/RBV. Genotyping of nine IL-6 variants were done by real -time PCR and genotyping of TLRs polymorphisms were done by RFLP-PCR. RESULTS: High frequency of TLR3 rs3775290 C/C genotype and TLR4 rs4986790 A/A genotype were noticed among patients with sustained viral response compared to Non-responder patients. The genetic association of TLR3 and TLR4 variants was evidenced by the improvement in the kinetics of viral load decline, with superiority of TLR3 compared to TLR4. Among, nine polymorphisms studied on IL-6 only rs1800796, rs2069845 and rs1880242 were associated with sustained viral response. Our study reports also that the common favourable IL-28B variant is essential for TLR-activated antiviral protection. CONCLUSION: TLR3 and TLR4 are involved in the pathogenesis of viral infections. TLR3 may be better suited than TLR4 to activate anti-viral program. Moreover, we propose that the Th2 cytokine, IL-6, constitutes a determinant of the outcome of therapy in HCV patients.
OBJECTIVES: TLRs are one of the most studied families of pathogen recognition receptors (PRRs) and play a pivotal role during HCV infection. The binding of ligands to TLRs on antigen presenting cells (APCs) leads to secretion of inflammatory cytokines, such as IL6, and induction of the acquired immunity response. Therefore, it has become necessarily to harness the TLRs properties' on therapeutically tools to enhance the HCV treatment response. Herein, we investigated the association between TLR3, TLR4 variants and nine IL-6 polymorphisms, and response to anti-viral treatment during HCV infection. METHODS: Study subjects comprised 120 patients infected with HCV-1b and treated with Peg-IFN/RBV. Genotyping of nine IL-6 variants were done by real -time PCR and genotyping of TLRs polymorphisms were done by RFLP-PCR. RESULTS: High frequency of TLR3rs3775290 C/C genotype and TLR4rs4986790 A/A genotype were noticed among patients with sustained viral response compared to Non-responder patients. The genetic association of TLR3 and TLR4 variants was evidenced by the improvement in the kinetics of viral load decline, with superiority of TLR3 compared to TLR4. Among, nine polymorphisms studied on IL-6 only rs1800796, rs2069845 and rs1880242 were associated with sustained viral response. Our study reports also that the common favourable IL-28B variant is essential for TLR-activated antiviral protection. CONCLUSION:TLR3 and TLR4 are involved in the pathogenesis of viral infections. TLR3 may be better suited than TLR4 to activate anti-viral program. Moreover, we propose that the Th2 cytokine, IL-6, constitutes a determinant of the outcome of therapy in HCV patients.