1887

Abstract

Several clinical observations point to an intricate crosstalk between iron (Fe) metabolism and chronic hepatitis C virus (HCV) infection. In this study, we wanted to investigate the molecular control that Fe levels exert on HCV replication at the hepatocyte level. In keeping with previous observations we confirmed that supra-physiological intracellular Fe induced by haemin treatment down-modulated HCV replication from subgenomic replicons. We also found that RNAi-mediated knockdown of the key Fe modulator hepcidin increased intracellular ferritin and inhibited HCV replication. Conversely, HCV replication did not modulate ferritin content in hepatocytes. Finally, we demonstrated that hepcidin is modulated at the mRNA level by alpha interferon through STAT3. We propose that in Huh7 cells hepcidin modulation leads to an unfavourable intracellular environment for HCV replication. These data may therefore contribute to a better understanding of the complex interplay between HCV and cellular physiology during infection.

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2011-09-01
2024-04-25
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References

  1. Abboud S., Haile D. J. 2000; A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–19912 [View Article][PubMed]
    [Google Scholar]
  2. Alter M. J. 2007; Epidemiology of hepatitis C virus infection. World J Gastroenterol 13:2436–2441[PubMed] [CrossRef]
    [Google Scholar]
  3. Andriopoulos B. Jr, Corradini E., Xia Y., Faasse S. A., Chen S., Grgurevic L., Knutson M. D., Pietrangelo A., Vukicevic S. et al. 2009; BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41:482–487 [View Article][PubMed]
    [Google Scholar]
  4. Babitt J. L., Huang F. W., Wrighting D. M., Xia Y., Sidis Y., Samad T. A., Campagna J. A., Chung R. T., Schneyer A. L. et al. 2006; Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38:531–539 [View Article][PubMed]
    [Google Scholar]
  5. Bassett S. E., Di Bisceglie A. M., Bacon B. R., Sharp R. M., Govindarajan S., Hubbard G. B., Brasky K. M., Lanford R. E. 1999; Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees. Hepatology 29:1884–1892 [View Article][PubMed]
    [Google Scholar]
  6. Bonkovsky H. L. 2002; Iron as a comorbid factor in chronic viral hepatitis. Am J Gastroenterol 97:1–4 [View Article][PubMed]
    [Google Scholar]
  7. Bonkovsky H. L., Naishadham D., Lambrecht R. W., Chung R. T., Hoefs J. C., Nash S. R., Rogers T. E., Banner B. F., Sterling R. K. et al. 2006; Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 131:1440–1451 [View Article][PubMed]
    [Google Scholar]
  8. Boucher E., Bourienne A., Adams P., Turlin B., Brissot P., Deugnier Y. 1997; Liver iron concentration and distribution in chronic hepatitis C before and after interferon treatment. Gut 41:115–120 [View Article][PubMed]
    [Google Scholar]
  9. Cho H., Lee H. C., Jang S. K., Kim Y. K. 2008; Iron increases translation initiation directed by internal ribosome entry site of hepatitis C virus. Virus Genes 37:154–160 [View Article][PubMed]
    [Google Scholar]
  10. Choo Q. L., Kuo G., Weiner A. J., Overby L. R., Bradley D. W., Houghton M. 1989; Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362 [View Article][PubMed]
    [Google Scholar]
  11. De Marco A., Dans P. D., Knezevich A., Maiuri P., Pantano S., Marcello A. 2010; Subcellular localization of the interaction between the human immunodeficiency virus transactivator Tat and the nucleosome assembly protein 1. Amino Acids 38:1583–1593 [View Article][PubMed]
    [Google Scholar]
  12. Desai T. K., Jamil L. H., Balasubramaniam M., Koff R., Bonkovsky H. L. 2008; Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Dig Dis Sci 53:815–822 [View Article][PubMed]
    [Google Scholar]
  13. Di Bisceglie A. M., Axiotis C. A., Hoofnagle J. H., Bacon B. R. 1992; Measurements of iron status in patients with chronic hepatitis. Gastroenterology 102:2108–2113[PubMed]
    [Google Scholar]
  14. Di Bona D., Cippitelli M., Fionda C., Cammà C., Licata A., Santoni A., Craxì A. 2006; Oxidative stress inhibits IFN-α-induced antiviral gene expression by blocking the JAK-STAT pathway. J Hepatol 45:271–279 [View Article][PubMed]
    [Google Scholar]
  15. Distante S., Bjøro K., Hellum K. B., Myrvang B., Berg J. P., Skaug K., Raknerud N., Bell H. 2002; Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 22:269–275 [View Article][PubMed]
    [Google Scholar]
  16. Donovan A., Brownlie A., Zhou Y., Shepard J., Pratt S. J., Moynihan J., Paw B. H., Drejer A., Barut B. et al. 2000; Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781 [View Article][PubMed]
    [Google Scholar]
  17. Feder J. N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D. A., Basava A., Dormishian F., Domingo R. Jr, Ellis M. C. et al. 1996; A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408 [View Article][PubMed]
    [Google Scholar]
  18. Fillebeen C., Pantopoulos K. 2010; Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells. J Hepatol 53:995–999 [View Article][PubMed]
    [Google Scholar]
  19. Fillebeen C., Pantopoulos K. 2011; Reply to: is there any association between HCV multiplication and iron induced liver injury in chronic hepatitis C?. J Hepatol [View Article][PubMed]
    [Google Scholar]
  20. Fillebeen C., Rivas-Estilla A. M., Bisaillon M., Ponka P., Muckenthaler M., Hentze M. W., Koromilas A. E., Pantopoulos K. 2005; Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C Virus. J Biol Chem 280:9049–9057 [View Article][PubMed]
    [Google Scholar]
  21. Fillebeen C., Muckenthaler M., Andriopoulos B., Bisaillon M., Mounir Z., Hentze M. W., Koromilas A. E., Pantopoulos K. 2007; Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J Hepatol 47:12–22 [View Article][PubMed]
    [Google Scholar]
  22. Fleming M. D., Trenor C. C. III, Su M. A., Foernzler D., Beier D. R., Dietrich W. F., Andrews N. C. 1997; Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 16:383–386[PubMed]
    [Google Scholar]
  23. Franchini M., Targher G., Capra F., Montagnana M., Lippi G. 2008; The effect of iron depletion on chronic hepatitis C virus infection. Hepatol Int 2:335–340 [View Article][PubMed]
    [Google Scholar]
  24. Fujita N., Sugimoto R., Urawa N., Araki J., Mifuji R., Yamamoto M., Horiike S., Tanaka H., Iwasa M. et al. 2007; Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 22:1886–1893 [View Article][PubMed]
    [Google Scholar]
  25. Fujita N., Sugimoto R., Motonishi S., Tomosugi N., Tanaka H., Takeo M., Iwasa M., Kobayashi Y., Hayashi H., Kaito M. 2008; Patients with chronic hepatitis C achieving a sustained virological response to peginterferon and ribavirin therapy recover from impaired hepcidin secretion. J Hepatol 49:702–710 [View Article][PubMed]
    [Google Scholar]
  26. Ganz T. 2006; Hepcidin – a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol 306:183–198 [View Article][PubMed]
    [Google Scholar]
  27. Hentze M. W., Muckenthaler M. U., Andrews N. C. 2004; Balancing acts: molecular control of mammalian iron metabolism. Cell 117:285–297 [View Article][PubMed]
    [Google Scholar]
  28. Hoenninger V. M., Rouha H., Orlinger K. K., Miorin L., Marcello A., Kofler R. M., Mandl C. W. 2008; Analysis of the effects of alterations in the tick-borne encephalitis virus 3′-noncoding region on translation and RNA replication using reporter replicons. Virology 377:419–430 [View Article][PubMed]
    [Google Scholar]
  29. Hou W. H., Rossi L., Shan Y., Zheng J. Y., Lambrecht R. W., Bonkovsky H. L. 2009; Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells. World J Gastroenterol 15:4499–4510 [View Article][PubMed]
    [Google Scholar]
  30. Hou W., Tian Q., Zheng J., Bonkovsky H. L. 2010; Zinc mesoporphyrin induces rapid proteasomal degradation of hepatitis C nonstructural 5A protein in human hepatoma cells. Gastroenterology 138:1909–1919.e3 [View Article][PubMed]
    [Google Scholar]
  31. Indraccolo S., Pfeffer U., Minuzzo S., Esposito G., Roni V., Mandruzzato S., Ferrari N., Anfosso L., Dell’Eva R. et al. 2007; Identification of genes selectively regulated by IFNs in endothelial cells. J Immunol 178:1122–1135[PubMed] [CrossRef]
    [Google Scholar]
  32. Kato T., Date T., Miyamoto M., Sugiyama M., Tanaka Y., Orito E., Ohno T., Sugihara K., Hasegawa I. et al. 2005; Detection of anti-hepatitis C virus effects of interferon and ribavirin by a sensitive replicon system. J Clin Microbiol 43:5679–5684 [View Article][PubMed]
    [Google Scholar]
  33. Kato T., Date T., Murayama A., Morikawa K., Akazawa D., Wakita T. 2006; Cell culture and infection system for hepatitis C virus. Nat Protoc 1:2334–2339 [View Article][PubMed]
    [Google Scholar]
  34. Koutsoudakis G., Kaul A., Steinmann E., Kallis S., Lohmann V., Pietschmann T., Bartenschlager R. 2006; Characterization of the early steps of hepatitis C virus infection by using luciferase reporter viruses. J Virol 80:5308–5320 [View Article][PubMed]
    [Google Scholar]
  35. Lambrecht R. W., Sterling R. K., Naishadham D., Stoddard A. M., Rogers T., Morishima C., Morgan T. R., Bonkovsky H. L. HALT-C Trial Group 2011; Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 140:1490–1500.e3 [View Article][PubMed]
    [Google Scholar]
  36. Lauer G. M., Walker B. D. 2001; Hepatitis C virus infection. N Engl J Med 345:41–52 [View Article][PubMed]
    [Google Scholar]
  37. Lin C. C., Yin M. C. 2008; Vitamins B depletion, lower iron status and decreased antioxidative defense in patients with chronic hepatitis C treated by pegylated interferon alfa and ribavirin. Clin Nutr 28:34–38[PubMed] [CrossRef]
    [Google Scholar]
  38. McKie A. T., Marciani P., Rolfs A., Brennan K., Wehr K., Barrow D., Miret S., Bomford A., Peters T. J. et al. 2000; A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309 [View Article][PubMed]
    [Google Scholar]
  39. Miorin L., Maiuri P., Hoenninger V. M., Mandl C. W., Marcello A. 2008; Spatial and temporal organization of tick-borne encephalitis flavivirus replicated RNA in living cells. Virology 379:64–77 [View Article][PubMed]
    [Google Scholar]
  40. Miura K., Taura K., Kodama Y., Schnabl B., Brenner D. A. 2008; Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 48:1420–1429 [View Article][PubMed]
    [Google Scholar]
  41. Nemeth E., Valore E. V., Territo M., Schiller G., Lichtenstein A., Ganz T. 2003; Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–2463 [View Article][PubMed]
    [Google Scholar]
  42. Nishina S., Hino K., Korenaga M., Vecchi C., Pietrangelo A., Mizukami Y., Furutani T., Sakai A., Okuda M. et al. 2008; Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134:226–238 [View Article][PubMed]
    [Google Scholar]
  43. Olynyk J. K., Reddy K. R., Di Bisceglie A. M., Jeffers L. J., Parker T. I., Radick J. L., Schiff E. R., Bacon B. R. 1995; Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 108:1104–1109 [View Article][PubMed]
    [Google Scholar]
  44. Paeshuyse J., Coelmont L., Vliegen I., Van hemel J., Vandenkerckhove J., Peys E., Sas B., De Clercq E., Neyts J. 2006; Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin. Biochem Biophys Res Commun 348:139–144 [View Article][PubMed]
    [Google Scholar]
  45. Papanikolaou G., Samuels M. E., Ludwig E. H., MacDonald M. L., Franchini P. L., Dubé M. P., Andres L., MacFarlane J., Sakellaropoulos N. et al. 2004; Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82 [View Article][PubMed]
    [Google Scholar]
  46. Pegoraro G., Marcello A., Myers M. P., Giacca M. 2006; Regulation of adeno-associated virus DNA replication by the cellular TAF-I/set complex. J Virol 80:6855–6864 [View Article][PubMed]
    [Google Scholar]
  47. Pietrangelo A. 2003; Hemochromatosis gene modifies course of hepatitis C viral infection. Gastroenterology 124:1509–1523 [View Article][PubMed]
    [Google Scholar]
  48. Shan Y., Lambrecht R. W., Donohue S. E., Bonkovsky H. L. 2006; Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin. FASEB J 20:2651–2653 [View Article][PubMed]
    [Google Scholar]
  49. Shan Y., Zheng J., Lambrecht R. W., Bonkovsky H. L. 2007; Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes. Gastroenterology 133:1166–1174 [View Article][PubMed]
    [Google Scholar]
  50. Sherrington C. A., Olynyk J. K. 2002; Iron as a cofactor in chronic hepatitis C infection. Liver 22:187–189 [View Article][PubMed]
    [Google Scholar]
  51. Sikorska K., Stalke P., Bielawski K. P. 2011; Is there any association between HCV multiplication and iron induced liver injury in chronic hepatitis C?. J Hepatol [View Article][PubMed]
    [Google Scholar]
  52. Sklan E. H., Charuworn P., Pang P. S., Glenn J. S. 2009; Mechanisms of HCV survival in the host. Nat Rev Gastroenterol Hepatol 6:217–227 [View Article][PubMed]
    [Google Scholar]
  53. Souza R. M., Freitas L. A., Lyra A. C., Moraes C. F., Braga E. L., Lyra L. G. 2006; Effect of iron overload on the severity of liver histologic alterations and on the response to interferon and ribavirin therapy of patients with hepatitis C infection. Braz J Med Biol Res 39:79–83 [View Article][PubMed]
    [Google Scholar]
  54. Tai A. W., Benita Y., Peng L. F., Kim S. S., Sakamoto N., Xavier R. J., Chung R. T. 2009; A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. Cell Host Microbe 5:298–307 [View Article][PubMed]
    [Google Scholar]
  55. Tenhunen R., Tokola O., Lindén I. B. 1987; Haem arginate: a new stable haem compound. J Pharm Pharmacol 39:780–786 [View Article][PubMed]
    [Google Scholar]
  56. Theurl I., Zoller H., Obrist P., Datz C., Bachmann F., Elliott R. M., Weiss G. 2004; Iron regulates hepatitis C virus translation via stimulation of expression of translation initiation factor 3. J Infect Dis 190:819–825 [View Article][PubMed]
    [Google Scholar]
  57. Torti F. M., Torti S. V. 2002; Regulation of ferritin genes and protein. Blood 99:3505–3516 [View Article][PubMed]
    [Google Scholar]
  58. Van Thiel D. H., Friedlander L., Fagiuoli S., Wright H. I., Irish W., Gavaler J. S. 1994; Response to interferon α therapy is influenced by the iron content of the liver. J Hepatol 20:410–415 [View Article][PubMed]
    [Google Scholar]
  59. Vardabasso C., Manganaro L., Lusic M., Marcello A., Giacca M. 2008; The histone chaperone protein nucleosome assembly protein-1 (hNAP-1) binds HIV-1 Tat and promotes viral transcription. Retrovirology 5:8 [View Article][PubMed]
    [Google Scholar]
  60. Verga Falzacappa M. V., Vujic Spasic M., Kessler R., Stolte J., Hentze M. W., Muckenthaler M. U. 2007; STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109:353–358 [View Article][PubMed]
    [Google Scholar]
  61. Wakita T., Pietschmann T., Kato T., Date T., Miyamoto M., Zhao Z., Murthy K., Habermann A., Kräusslich H. G. et al. 2005; Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796 [View Article][PubMed]
    [Google Scholar]
  62. Walker E. M. Jr, Walker S. M. 2000; Effects of iron overload on the immune system. Ann Clin Lab Sci 30:354–365[PubMed]
    [Google Scholar]
  63. Yang C. H., Wei L., Pfeffer S. R., Du Z., Murti A., Valentine W. J., Zheng Y., Pfeffer L. M. 2007; Identification of CXCL11 as a STAT3-dependent gene induced by IFN. J Immunol 178:986–992[PubMed] [CrossRef]
    [Google Scholar]
  64. Zhu H., Zhao H., Collins C. D., Eckenrode S. E., Run Q., McIndoe R. A., Crawford J. M., Nelson D. R., She J. X., Liu C. 2003; Gene expression associated with interferon alfa antiviral activity in an HCV replicon cell line. Hepatology 37:1180–1188 [View Article][PubMed]
    [Google Scholar]
  65. Zhu H., Shang X., Terada N., Liu C. 2004; STAT3 induces anti-hepatitis C viral activity in liver cells. Biochem Biophys Res Commun 324:518–528 [View Article][PubMed]
    [Google Scholar]
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