Volume 96, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Toll-like receptors (TLRs) are recognized as fundamental contributors to the immune system function against infections. Hepatitis C virus (HCV) infection represents a global health problem especially in Egypt having the highest HCV prevalence worldwide where HCV infection is a continuing epidemic. The aim of the present study was to investigate the possible association between genetic variation in TLR-3 and TLR-9 and HCV infection and hepatic fibrosis in chronic HCV-positive Egyptian patients. The present study included 100 naïve chronic HCV-positive patients and 100 age- and sex-matched healthy controls. Genotyping of TLR-3 (_7 C/A [rs3775296]), TLR-3 (c.1377C/T [rs3775290]) and TLR-9 (1237T/C [rs5743836]) were done by polymerase chain reaction restriction fragment length polymorphism technique. Frequency of polymorphic genotypes in TLR-3 (_7 C/A), TLR-3 (c.1377C/T) and TLR-9 (1237T/C) were not significantly different between studied HCV-positive patients and controls with values 0.121, 0.112, and 0.683, respectively. TLR-3 c.1377 T-allele was associated with advanced stage of hepatic fibrosis ( = 0.003).


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  1. El-Zanaty F, Way A, , 2009. Egypt Demographic and Health Survey 2008. Cairo, Egypt: Ministry of Health, El Zanaty and Associates, and Macro International. Available at: http://dhsprogram.com/pubs/pdf/FR220/FR220.pdf. Accessed May 17, 2013. [Google Scholar]
  2. Visvanathan K, Lewin SR, , 2006. Immunopathogenesis: role of innate and adaptive immune responses. Semin Liver Dis 26: 104115.[Crossref] [Google Scholar]
  3. Bertoletti A, Gehring AJ, , 2006. The immune response during hepatitis B virus infection. J Gen Virol 87: 14391449.[Crossref] [Google Scholar]
  4. Akira S, Takeda K, , 2004. Toll-like receptor signaling. Nat Rev Immunol 4: 499511.[Crossref] [Google Scholar]
  5. Isaza-Correa JM, Liang Z, van den Berg A, Diepstra A, Visser L, , 2014. Toll-like receptors in the pathogenesis of human B cell malignancies. J Hematol Oncol 7: 57.[Crossref] [Google Scholar]
  6. O'Neill LA, Bowie AG, , 2007. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7: 353364.[Crossref] [Google Scholar]
  7. Krishnegowda G, Hajjar AM, Zhu J, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC, , 2005. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem 280: 86068616.[Crossref] [Google Scholar]
  8. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S, , 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408: 740745.[Crossref] [Google Scholar]
  9. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S, , 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3: 196200.[Crossref] [Google Scholar]
  10. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB, , 2003. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 100: 66466651.[Crossref] [Google Scholar]
  11. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S, , 2003. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33: 29872997.[Crossref] [Google Scholar]
  12. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA, , 2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413: 732738.[Crossref] [Google Scholar]
  13. Ahmad-Nejad P, Häcker H, Rutz M, Bauer S, Vabulas RM, Wagner H, , 2002. Bacterial CpG-DNA and lipopolysaccharidesactivate Toll-like receptors at distinct cellular compartments. Eur J Immunol 32: 19581968.[Crossref] [Google Scholar]
  14. Kaisho T, Akira S, , 2001. Toll-like receptors and their signaling mechanism in innate immunity. Acta Odontol Scand 59: 124130.[Crossref] [Google Scholar]
  15. Lu KC, Yang HY, Lin YF, Kao SY, Lai CH, Chu CM, Wu CC, Su SL, , 2011. The T-1237C polymorphism of the Toll-like receptor-9 gene is associated with chronic kidney disease in a Han Chinese population. Tohoku J Exp Med 225: 109116.[Crossref] [Google Scholar]
  16. Akira S, Uematsu S, Takeuchi O, , 2006. Pathogen recognition and innate immunity. Cell 124: 783801.[Crossref] [Google Scholar]
  17. Nagano Y, Kojima Y, , 1954. Immunizing property of vaccinia virus inactivated by ultraviolets rays. C R Seances Soc Biol Fil 148: 17001702. [Google Scholar]
  18. Lindenmann J, Burke DC, Isaacs A, , 1957. Studies on the production, mode of action and properties of interferon. Br J Exp Pathol 38: 551562. [Google Scholar]
  19. Pestka S, Krause CD, Walter MR, , 2004. Interferons, interferon like cytokines, and their receptors. Immunol Rev 202: 832.[Crossref] [Google Scholar]
  20. Trinchieri G, , 2010. Type I interferon: friend or foe? J Exp Med 207: 20532063.[Crossref] [Google Scholar]
  21. Liu F, Lu W, Qian Q, Qi W, Hu J, Feng B, , 2012. Frequency of TLR 2, 4, and 9 gene polymorphisms in Chinese population and their susceptibility to type 2 diabetes and coronary artery disease. J Biomed Biotechnol 2012: 373945. [Google Scholar]
  22. Yang HY, Lee HS, Lee CH, Fang WH, Chen HC, Salter DM, Su SL, , 2013. Association of a functional polymorphism in the promoter region of TLR-3 with osteoarthritis: a two-stage case-control study. J Orthop Res 31: 680685.[Crossref] [Google Scholar]
  23. Heinz S, Haehnel V, Karaghiosoff M, Schwarzfischer L, Müller M, Krause SW, Rehli M, , 2003. Species specific regulation of Toll-like receptor 3 genes in men and mice. J Biol Chem 278: 2150221509.[Crossref] [Google Scholar]
  24. Lange NE, Zhou X, Lasky-Su J, Himes BE, Lazarus R, Manuel Soto-Quirós M, Avila L, Celedón JC, Hawrylowicz CM, Raby BA, Litonjua AA, , 2011. Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes. BMC Med Genet 12: 26.[Crossref] [Google Scholar]
  25. Carvalho A, Osorio NS, Saraiva M, Cunha C, Almeida AJ, Teixeira-Coelho M, Ludovico P, Pedrosa J, Pitzurra L, Aversa F, Romani L, Castro AG, , 2011. The C allele of rs5743836 polymorphism in the human TLR9 promoter links IL-6 and TLR9 up-regulation and confers increased B-cell proliferation. PLoS One 6: e28256.[Crossref] [Google Scholar]
  26. Ng MT, Van't Hof R, Crockett JC, Hope ME, Berry S, Thomson J, McLean MH, McColl KE, El-Omar EM, Hold GL, , 2010. Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9-1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease. Infect Immun 78: 13451352.[Crossref] [Google Scholar]
  27. Mostafa I, Abd el Aal M, Syam M, , 2005. HCV recurrence in adult living related transplantation: initial results of starting population. Liver Transpl 11: 456462.[Crossref] [Google Scholar]
  28. Tuite A, Gros P, , 2006. The impact of genomics on the analysis of host resistance to infectious disease. Microbes Infect 8: 16471653.[Crossref] [Google Scholar]
  29. Clementi M, Di Gianantonio E, , 2006. Genetic susceptibility to infectious diseases. Reprod Toxicol 21: 345349.[Crossref] [Google Scholar]
  30. Bedossa P, Poynard T, The METAVIR Cooperative Study Group; , 1996. An algorithm for the grading of activity in chronic hepatitis C. Hepatology 24: 289293.[Crossref] [Google Scholar]
  31. Cheng PL, Eng HL, Chou MH, You HL, Lin TM, , 2007. Genetic polymorphisms of viral infection-associated Toll-like receptors in Chinese population. Transl Res 150: 311318.[Crossref] [Google Scholar]
  32. Schröder NW, Schumann RR, , 2005. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5: 156164.[Crossref] [Google Scholar]
  33. Turvey SE, Hawn TR, , 2006. Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections. Clin Immunol 120: 19.[Crossref] [Google Scholar]
  34. Zhou J, Huang Y, Tian D, Xu D, Chen M, Wu H, , 2009. Expression of Toll-like receptor 9 in peripheral blood mononuclear cells from patients with different hepatitis B and C viral loads. J Huazhong Univ Sci Technol 29: 313317.[Crossref] [Google Scholar]
  35. Broering R, Wu J, Meng Z, Hilgard P, Lu M, Trippler M, Szczeponek A, Gerken G, Schlaak JF, , 2008. Toll-like receptor-stimulated non-parenchymal liver cells can regulate hepatitis C virus replication. J Hepatol 48: 914922.[Crossref] [Google Scholar]
  36. Hu K, Wang GW, Wang ZH, , 2011. TLR9 mRNA expression and tumor necrosis factor alpha/interleukin-6 secretion in murine microglia by hepatitis C virus stimulation. Zhonghua Yi Xue Za Zhi 91: 10701074. [Google Scholar]
  37. Zhao P, Ma L, Ji H, Yu L, Feng J, Wang J, Liu MY, Jiang YF, , 2015. The expression of TLR-9, CD86, and CD95 phenotypes in circulating B cells of patients with chronic viral hepatitis B or C before and after antiviral therapy. Mediators Inflamm 2015: 762709. [Google Scholar]
  38. Wei XS, Wei CD, Tong YQ, Zhu CL, Zhang PA, , 2014. Single nucleotide polymorphisms of toll-like receptor 7 and toll-like receptor 9 in hepatitis C virus infection patients from central China. Yonsei Med J 55: 428434.[Crossref] [Google Scholar]
  39. Tanabe M, Kurita-Taniguchi M, Takeuchi K, Takeda M, Ayata M, Oyura H, Matsumoto M, Seya T, , 2003. Mechanism of up-regulation of human Toll-like receptor receptor 3 secondary to infection of measles virus-attenuated strains. Biochem Biophys Res Commun 311: 3948.[Crossref] [Google Scholar]
  40. Medhi S, Deka M, Deka P, Swargiary SS, Hazam RK, Sharma MP, Gumma PK, Asim M, Kar P, , 2011. Promoter region polymorphism and expression profile of toll like receptor-3 (TLR-3) gene in chronic hepatitis C virus (HCV) patients from India. Indian J Med Res 134: 200207. [Google Scholar]
  41. Askar E, Bregadze R, Mertens J, Schweyer S, Rosenberger A, Ramadori G, Mihm S, , 2009. TLR3 gene polymorphisms and liver disease manifestations in chronic hepatitis C. J Med Virol 81: 12041211.[Crossref] [Google Scholar]
  42. Lee YA, Wallace MC, Friedman SL, , 2015. Pathobiology of liver fibrosis: a translational success story. Gut 64: 830841.[Crossref] [Google Scholar]
  43. Seki E, Schwabe RF, , 2015. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61: 10661079.[Crossref] [Google Scholar]
  44. Seki E, Brenner DA, , 2008. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48: 322335.[Crossref] [Google Scholar]
  45. Szabo G, Dolganiuc A, Mandrekar P, , 2006. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 44: 287298.[Crossref] [Google Scholar]
  46. Mencin A, Kluwe J, Schwabe RF, , 2009. Toll-like receptors as targets in chronic liver diseases. Gut 58: 704720.[Crossref] [Google Scholar]
  47. Khvalevsky E, Rivkin L, Rachmilewitz J, Galun E, Giladi H, , 2007. TLR3 signaling in a hepatoma cell line is skewed towards apoptosis. J Cell Biochem 100: 13011312.[Crossref] [Google Scholar]
  48. Wang B, Trippler M, Pei R, Lu M, Broering R, Gerken G, Schlaak JF, , 2009. Toll-like receptor activated human and murine hepatic stellate cells are potent regulators of hepatitis C virus replication. J Hepatol 51: 10371045.[Crossref] [Google Scholar]
  49. Xiao X, Zhao P, Rodriguez-Pinto D, Qi D, Henegariu O, Alexopoulou L, Flavell RA, Wong FS, Wen L, , 2009. Inflammatory regulation by TLR3 in acute hepatitis. J Immunol 183: 37123719.[Crossref] [Google Scholar]
  50. Nakamura M, Funami K, Komori A, Yokoyama T, Aiba Y, Araki A, Takii Y, Ito M, Matsuyama M, Koyabu M, Migita K, Taniguchi K, Fujioka H, Yatsuhashi H, Matsumoto M, Ishibashi H, Seya T, , 2008. Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers. Hepatol Int 2: 222230.[Crossref] [Google Scholar]
  51. Gardner T, Chen Q, Jin Y, Ajuber M, , 2010. Toll-like receptor 3 ligand dampens liver inflammation by stimulating Valpha14 invariant natural killer T cells to negatively regulate gamma/delta T cells. Am J Pathol 176: 17791789.[Crossref] [Google Scholar]
  52. Yin S, Gao B, , 2010. Toll-like receptor 3 in liver diseases. Gastroenterol Res Pract 2010: 971270.[Crossref] [Google Scholar]
  53. Dong Z, Wei H, Sun R, Hu Z, Gao B, Tian Z, , 2004. Involvement of natural killer cells in PolyI:C-induced liver injury. J Hepatolology 41: 966973.[Crossref] [Google Scholar]
  54. Jeong WI, Park O, Radaeva S, Gao B, , 2006. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology 44: 14411451.[Crossref] [Google Scholar]
  55. Byun JS, Suh YG, Yi HS, Lee YS, Jeong WI, , 2013. Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. J Hepatolology 58: 342349.[Crossref] [Google Scholar]
  56. Seo W, Eun HS, Kim SY, Yi HS, Lee YS, Park SH, Jang MJ, Jo E, Kim SC, Han YM, Park KG, Jeong WI, , 2016. Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis. Hepatology 64: 616631.[Crossref] [Google Scholar]
  57. Dejager L, Libert C, , 2008. Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in d-galactosamine-sensitized mice. Cytokine 42: 5561.[Crossref] [Google Scholar]
  58. Hu KQ, Kyulo NL, Lim N, Elhazin B, Hillebrand DJ, Bock T, , 2004. Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol 99: 860865.[Crossref] [Google Scholar]
  59. Firdaus R, Biswas A, Saha K, Mukherjee A, Pal F, Chaudhuri S, Chandra A, Konar A, Sadhukhan PC, , 2014. Modulation of TLR 3, 7 and 8 expressions in HCV genotype 3 infected individuals: potential correlations of pathogenesis and spontaneous clearance. Biomed Res Int 2014: 491064.[Crossref] [Google Scholar]
  60. Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL, , 2000. Genetic epidemiology of hepatitis C virus throughout Egypt. J Infect Dis 182: 698707.[Crossref] [Google Scholar]
  61. Dusheiko GM, Schmilovitz-Weiss H, Brown D, McOmish F, Yap PL, Sherlock S, McIntyre N, Simmonds P, , 1994. Hepatitis C virus genotypes: an investigation of type-specific differences in geographic origin and disease. Hepatology 19: 1318.[Crossref] [Google Scholar]
  62. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK, , 1998. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 339: 14851492.[Crossref] [Google Scholar]
  63. Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, Shibata M, Morishima T, , 1992. Detection of hepatitis C virus by polymerase chain reaction and response to interferon alpha therapy: relationship to genotypes of hepatitis C virus. Hepatology 16: 293299.[Crossref] [Google Scholar]
  64. Zein NN, Rakela J, Krawitt EL, Reddy KR, Tominaga T, Persing DH, , 1996. Hepatitis C virus genotypes in the United States: epidemiology, pathogenicity, and response to interferon therapy. Ann Intern Med 125: 634639.[Crossref] [Google Scholar]

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  • Received : 07 Aug 2016
  • Accepted : 18 Nov 2016
  • Published online : 16 Jan 2017

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