Immunologic Research

, 30:15 | Cite as

Manipulation of iron to determine survival

Competition between host and pathogen
  • Nihay Laham
  • Rachel Ehrlich
Article

Abstract

Iron is an essential nutrient that can determine cellular survival. Many organisms have evolved sophisticated mechanisms for iron uptake and transport to support their growth. The dual dependence on iron of both the host and invading pathogen initiates a competition for this nutrient following infection. Microorganisms have developed various strategies to acquire iron from the host. These are counter-balanced by an iron-withholding strategy that the host deploys as part of its defense system. This strategy, involving many iron-regulatory proteins, mediates iron depletion at the mucosal surfaces, in the extracellular environment, and within the cells. Iron is sequestered into storage by the host in order to deprive the pathogens of this factor and to prevent their proliferation. This system can be compromised. In particular, new evidence is emerging that suggests that viruses are able to specifically target and regulate proteins involved in iron homeostasis. This review focuses on the procedures employed by the host and viruses to regulate iron as a means of defense and survival, respectively.

Key Words

Iron metabolism Host defense Intections Viral proteins HFE 

References

  1. 1.
    Weinberg ED: The role of iron in protozoan and fungal infectious diseases. J Eukaryt Micro 1999;46:231–238.CrossRefGoogle Scholar
  2. 2.
    Aisen P, Enns C, Wessling-Resnick M: Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 2001;33:940–959.PubMedCrossRefGoogle Scholar
  3. 3.
    Lieu PT, Heiskala M, Peterson PA, Yang Y: The roles of iron in health and disease. Mol Asp Med 2001;22:1–87.CrossRefGoogle Scholar
  4. 4.
    van Vliet AH, Ketley JM, Park SF, Penn CW: The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense. FEMS Micro Rev 2002;26:173–186.Google Scholar
  5. 5.
    Boyer E, Bergevin I, Malo D, Gros P, Cellier MF: Acquisition of Mn(II) in addition to Fe(II) is required for full virulence of Salmonella enterica serovar Typhimurium. Infect Immun 2002;70:6032–6042.PubMedCrossRefGoogle Scholar
  6. 6.
    Marx JJM: Iron and infection: competition between host and microbes for a precious element. Best Prac Res Clin Haemat 2002;15:411–426.Google Scholar
  7. 7.
    Braun V, Braun M: Iron transport and signaling in Escherichia coli. FEBS Lett 2002;529:78–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Braun V, Braun M: Active transport of iron and siderophore antibiotics. Curr Opin Micro 2002;5:194–201.CrossRefGoogle Scholar
  9. 9.
    Brown JS, Holden DW: Iron acquisition by Gram-positive bacterial pathogens. Microb Infect 2002;4:1149–1156.CrossRefGoogle Scholar
  10. 10.
    Visca P, Leoni L, Wilson MJ, Lamont IL: Iron transport and regulation, cell signalling and genomics: lessons from Escherichia coli and Pseudomonas. Mol Microb 2002;45:1177–1190.CrossRefGoogle Scholar
  11. 11.
    Richardson DR, Ponka P: The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophys Acta 1997;1331:1–40.PubMedGoogle Scholar
  12. 12.
    Weinberg ED: Modulation of intramacrophage iron metabolism during microbial cell invasion. Microb Infect 2000;2:85–89.CrossRefGoogle Scholar
  13. 13.
    Mikulits W, Schranzhofer M, Beug H, Mullner EW: Post-transcriptional control via iron-responsive elements: the impact of aberrations in hereditary disease. Mutat Res 1999;437:219–230.PubMedCrossRefGoogle Scholar
  14. 14.
    Ehrlich R, Lemonnier FA: HFE—A novel nonclassical class I molecule that is involved in iron metabolism. Immunity 2000;13:585–588.PubMedCrossRefGoogle Scholar
  15. 15.
    Parkkila S, Niemela O, Britton RS, Fleming RE, Waheed A, Bacon BR, Sly WS: Molecular aspects of iron absorption and HFE expression. Gastroenterology 2001;121:1489–1496.PubMedCrossRefGoogle Scholar
  16. 16.
    Fleming RE, Sly WS: Mechanisms of iron accumulation in hereditary hemochromatosis. Ann Rev Physiol 2002;64:663–680.CrossRefGoogle Scholar
  17. 17.
    Ganz T: The role of hepcidin in iron sequestration during infections and in the pathogenesis of anemia of chronic disease. Is Med Assoc J 2002;4:1043–1045.Google Scholar
  18. 18.
    Philpott CC: Molecular aspects of iron absorption: Insights into the role of HFE in hemochromatosis. Hepatology 2002;35:993–1001.PubMedCrossRefGoogle Scholar
  19. 19.
    Pietrangelo A: Physiology of iron transport and the hemochromatosis gene. Am J Physiol Gastrointest Liver Physiol 2002;282:G403–414.PubMedGoogle Scholar
  20. 20.
    van Asbeck BS, Verbrugh HA, van Oost BA: Listeria monocytogenes meningits and decreased phagocytosis assoicated with iron overload. Br Med J 1982;284:542–544.Google Scholar
  21. 21.
    Weinberg ED: Iron loading and disease surveillance. Emerg Infect Dis 1999;5:346–352.PubMedCrossRefGoogle Scholar
  22. 22.
    Walker EM, Walker SM: Effects of iron overload on the immune system. Ann Clin Lab Sci 2000;30:354–365.PubMedGoogle Scholar
  23. 23.
    Lounis N, Truffot-Pernot C, Grosset J Gordeuk VR, Boelaert JR: Iron and Mycobacterium tuberculosis infection. J Clin Virol 2001;20:123–126.PubMedCrossRefGoogle Scholar
  24. 24.
    Barabino A: Helicobacter pylori-related iron deficiency anemia: a review. Helicobacter 2002;7:71–75.PubMedCrossRefGoogle Scholar
  25. 25.
    Ward PP, Mendoza-Meneses M, Cunningham GA, Conneely OM: Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol 2003;23:178–185.PubMedCrossRefGoogle Scholar
  26. 26.
    Levay PF, Viljoen M: Lactoferrin: a general review. Haematologica 1995;80:252–267.PubMedGoogle Scholar
  27. 27.
    Guillen C, McInnes IB, Brock JH: Iron in synovial fluid. Removal by lactoferrin and relationship to iron regulatory protein (IRP) activity. Adv Exp Med Biol 1998;443:161–165.PubMedGoogle Scholar
  28. 28.
    Mason PL, Hermans JF, Schonne E: Lactoferrin, an iron-binding protein in neutrophil leukocytes. J Exp Med 1969;130:643–658.CrossRefGoogle Scholar
  29. 29.
    Brock JH: The physiology of lactoferrin. Biochem Cell Biol 2002;80:1–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Potter BJ, Wang F: Molecular regulation of iron homeostasis and resistance to infection in alcoholics. Front Biosci 2002;7:d1396–1409.PubMedCrossRefGoogle Scholar
  31. 31.
    Lonnerdal B, Iyer S: Lactoferrin: molecular structure and biological function. Ann Rev Nutrit 1995; 15:93–110.CrossRefGoogle Scholar
  32. 32.
    Aguila A, Herrera AG, Morrison D, Cosgrove B, Perojo A, Montesinos I, et al.: Bacteriostatic activity of human lactoferrin against Staphylococcus aureus is a function of its iron-binding properties and is not influenced by antibiotic resistance. FEMS Immun Med Micro 2001;31:145–152.CrossRefGoogle Scholar
  33. 33.
    Schaible UE, Collins HL, Priem F, Kaufmann SH: Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J Exp Med 2002;196:1507–1513.PubMedCrossRefGoogle Scholar
  34. 34.
    Ellison RT, Giehl TJ, LaForce EM: Damage of the outer membrane of enteric Gram-negative bacteria by lactoferrin and transferrin. Infect Immun 1988;56:2774–2781.PubMedGoogle Scholar
  35. 35.
    Ellison RT, Giehl TJ: Killing of gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 1991;88:1080–1091.PubMedGoogle Scholar
  36. 36.
    Ward PP, Uribe-Luna S, Conneely OM: Lactoferrin and host defense. Biochem Cell Biol 2002;80:95102.CrossRefGoogle Scholar
  37. 37.
    Singh PK, Parsek MR, greenberg EP, Welsh MJ: A component of innate immunity prevents bacterial biofilm development. Nature 2002;417:552–555.PubMedCrossRefGoogle Scholar
  38. 38.
    Ikeda M, Sugiyama K, Tanaka T, Tanaka K, Sekihara H, Shimotohno K, Kato N: Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes. Biochem Biophys Res Commun 1998;245:549–553.PubMedCrossRefGoogle Scholar
  39. 39.
    Tanaka K, Ikeda M, Nozaki A, Kato N, Tsuda H, Saito S, Sekihara H: Lactoferrin inibits hepatitis C virus viremia in patients with chronic hepatitis C: a pilot study. Jap J Cancer Res 1999;90:367–371.Google Scholar
  40. 40.
    van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK: Antiviral activities of lactoferrin. Antiviral Res. 2001;52:225–239.PubMedCrossRefGoogle Scholar
  41. 41.
    Hara K, Ikeda M, Saito S, Matsumoto S, Numata K, Kato N, et al.: Lactoferrin inhibits hepatitis B virus infection in cultured human hepatocytes. Hepat Res 2002;24:228.CrossRefGoogle Scholar
  42. 42.
    Lin TY, Chu C, Chiu CH: Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro. J Infect Dis 2002;186: 1161–1164.PubMedCrossRefGoogle Scholar
  43. 43.
    Brittenham GM, Weiss G, Brissot P, Laine F, Guillygomarc’h A, Guyader D, et al.: Clinical consequences of new insights in the pathophysiology of disorders of iron and heme metabolism. Hematology (Am Soc Hematol Educ Program) 2000;39–50.Google Scholar
  44. 44.
    Yang F, Liu XB, Quinones M, Melby PC, Ghio A, Haile DJ: Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem 2002;277:39786–39791.PubMedCrossRefGoogle Scholar
  45. 45.
    Konijn AM, Carmel N, Levy R, Hershko C: Ferritin synthesis in inflammation. II. Mechanism of increased ferritin synthesis. Br J Haematol 1981;49:361–370.PubMedGoogle Scholar
  46. 46.
    Byrd TF, Horwitz MA: Chloroquine inhibits theintracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest 1991;88:351–357.PubMedGoogle Scholar
  47. 47.
    Gebran SJ, Newton C, Yamamoto Y, Widen R, Klein TW, Friedman H: Macrophage permissiveness for Legionella pneumophila growth modulated by iron. Infect Immun 1994;62:564–568.PubMedGoogle Scholar
  48. 48.
    Newman SL, Gootee L, Brunner G, Deepe GS, Jr.: Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis. J Clin Invest 1994;93:1422–1429.PubMedGoogle Scholar
  49. 49.
    Savarino A, Calosso L, Piragino A, Martini C, Gennero L, Pescarmona GP, Pugliese A: Modulation of surface transferrin receptors in lymphoid cells de novo infected with human immunodeficiency virus type-1. Cell Biochem Funct 1999;17:47–55.PubMedCrossRefGoogle Scholar
  50. 50.
    Lobmayr L, Sauer T, Killisch I, Schranzhofer M, Wilson RB, Ponka P, et al.: Transferrin receptor hyperexpression in primary erythroblasts is lost on transformation by avian erythroblastosis virus. Blood 2002;100:289–298.PubMedCrossRefGoogle Scholar
  51. 51.
    Byrd TF, Horwitz MA: Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. J Clin Invest 1989;83:1457–1465.PubMedGoogle Scholar
  52. 52.
    Byrd TF, Horwitz MA: Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma. J Clin Invest 1993;91:969–976.PubMedGoogle Scholar
  53. 53.
    Byrd TF, Horwitz MA: Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against Legionella pneumophila. J Clin Invest 1991;88:1103–1112.PubMedCrossRefGoogle Scholar
  54. 54.
    Torti SV, Kwak EL, Miller SC, Miller LL, Ringold GM, Myambo KB, et al.: The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene. J Biol Chem 1988;263:12638–12644.PubMedGoogle Scholar
  55. 55.
    Wei Y, Miller SC, Tsuji Y, Torti SV, Torti FM: Interleukin 1 induces ferritin heavy chain in human muscle cells. Biochem Biophys Res Commun 1990;169:289–296.PubMedCrossRefGoogle Scholar
  56. 56.
    Miller LL, Miller SC, Torti SV, Tsuji Y, Torti FM: Iron-independent induction of ferritin H chain by tumor necrosis factor. Proc Natl Acad Sci USA 1991;88:4946–4950.PubMedCrossRefGoogle Scholar
  57. 57.
    Bourgeade MF, Silbermann F, Kuhn L, Testa U, Peschle C, Memet S, et al.: Post-transcriptional regulation of transferrin receptor mRNA by IFN gamma. Nucleic Acids Res 1992;20:2997–3003.PubMedCrossRefGoogle Scholar
  58. 58.
    Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN: Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem 1990;265:14572–14578.PubMedGoogle Scholar
  59. 59.
    Rogers JT, Andriotakis JL, Lacroix L, Durmowicz GP, Kasschau KD, Bridges KR: Translational enhancement of H-ferritin mRNA by interleukin-1 beta acts through 5′ leader sequences distinct from the iron responsive element. Nucleic Acids Res 1994;22:2678–2686.PubMedCrossRefGoogle Scholar
  60. 60.
    Rogers JT: Ferritin translation by interleukin-1 and interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes. Blood 1996;87:2525–2537.PubMedGoogle Scholar
  61. 61.
    Govoni G, Gros P: Macrophage NRAMP1 and its role in resistance to microbial infections. Inflamm Res 1998;47:277–284.PubMedCrossRefGoogle Scholar
  62. 62.
    Barton CH, Biggs TE, Baker ST, Bowen H, Atkinson PG: Nramp1: a link between intracellular iron transport and innate resistance to intracelular pathogens. J Leuk Biol 1999;66:757–762.Google Scholar
  63. 63.
    Blackwell JM, Searle S, Mohamad H, White JK: Divalent cation transpor and susceptibility to infectious and autoimmune disease: continuation of the Ity/Lsh/Bcg/Nramp1/Slc11al gene story. Immunol Lett 2003;85:197–203.PubMedCrossRefGoogle Scholar
  64. 64.
    Govoni G, Vidal S, Cellier M, Lepage P, Malo D, Gros P: Genomic structure, promoter sequence, and induction of expression of the mouse Nramp1 gene in macrophages. Genomics 1995;27:9–19.PubMedCrossRefGoogle Scholar
  65. 65.
    Goyoni G, Gauthier S, Billia F, Iscove NN, Gros P: Cell-specific and inducible Nramp1 gene expression in mouse macrophages in vitro and in vivo. J Leuk Biol 1997;62:277–286.Google Scholar
  66. 66.
    Wyllie S, Seu P, Goss JA: The natural resistance-associated macrophage protein 1 S1c11al (formerly Nramp1) and iron metabolism in macrophages. Microb Infect 2002;4:351–359.CrossRefGoogle Scholar
  67. 67.
    Gruenheid S, Pinner E, Desjardins M, Gros P: Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J Exp Med 1997;185:717–730.PubMedCrossRefGoogle Scholar
  68. 68.
    Searle S, Bright NA, Roach TI, Atkinson PG, Barton CH, Meloen RH, Blackwell JM: Localisation of Nrampl in macrophages: modulation with activation and infection. J Cell Sci 1998;111:2855–2866.PubMedGoogle Scholar
  69. 69.
    Kuhn DE, Baker BD, Lafuse WP, Zwilling BS: Differential iron transport into phagosomes isolated from the RAW 264.7 macrophage cell lines transfected with Nrampl Gly 169 or Nrampl Asp 169. J Leuk Biol 1999;66:1113–1119.Google Scholar
  70. 70.
    Zwilling BS, Kuhn DE, Wikoff L, Brown D, Lafuse W: Role of iron in Nrampl-mediated inhibition of mycobacterial growth. Infect Immun 1999;67:1386–1392.PubMedGoogle Scholar
  71. 71.
    Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P, Grinstein S: Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nrampl) impairs phagosomal acidification. J Exp Med 1998;188:351–364.PubMedCrossRefGoogle Scholar
  72. 72.
    Biggs TE, Baker ST, Botham MS, Dhital A, Barton CH, Perry VH: Nrampl modulates iron homoeostasis in vivo and in vitro: evidence for a role in cellular iron release involving de-acidification of intracellular vesicles. Eur J Immun 2001;31:2060–2070.CrossRefGoogle Scholar
  73. 73.
    Gomes MS, Appelberg R: Evidence for a link between iron metabolism and Nrampl gene function in innate resistance against Mycobacterium avium. Immunol 1998;95:165–168.CrossRefGoogle Scholar
  74. 74.
    Cuellar-Mata P, Jabado N, Liu J, Furuya W, Finlay BB, Gros P, Grinstein S: Nrampl modifies the fusion of Salmonella typhimurium-containing vacuoles with cellular endomembranes in macrophages. J Biol Chem 2002;277:2258–2265.PubMedCrossRefGoogle Scholar
  75. 75.
    Frehel C, Canonne-Hergaux F, Gros P, De Chastellier C: Effect of Nrampl on bacterial replication and on maturation of Mycobacterium avium-containing phagosomes in bone marrow-derived mouse macrophages. Cellular Microbiol 2002;4:541–556.CrossRefGoogle Scholar
  76. 76.
    Gomes MS, Appelberg R: NRAMP1- or cytokine-induced bacteriostasis of Mycobacterium avium by mouse macrophages is independent of the respiratory burst. Microbiology 2002;148:3155–3160.PubMedGoogle Scholar
  77. 77.
    Zhong W, Lafuse W, Zwilling BS Infection with Mycobacterium avium differentially regulates the expression of iron transport protein mRNA in murine peritoneal macrophages. Infect Immun 2001;69:6618–6624.PubMedCrossRefGoogle Scholar
  78. 78.
    James SL: Role of nitric oxide in parasitic infections. Microbiol Rev 1995;59:533–547.PubMedGoogle Scholar
  79. 79.
    Brunet LR: Nitric oxide in parasitic infections. Int Immunopharm 2001;1:1457–1467.CrossRefGoogle Scholar
  80. 80.
    Bogdan C: Nitric oxide and the regulation of gene expression. Trend Cell Biol 2001;11:66–75.CrossRefGoogle Scholar
  81. 81.
    Eichenbaum Z, Muller E, Morse SA, Scott JR: Acquisition of iron from host proteins by the group A streptococcus. Infect Immun 1996;64:5428–5429.PubMedGoogle Scholar
  82. 82.
    Cooper CE, Lynagh GR, Hoyes KP, Hider RC, Cammack R, Porter JB: The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J Biol Chem 1996;271:20291–20299.PubMedCrossRefGoogle Scholar
  83. 83.
    Lamarche N, Matton G, Massie B, Fontecave M, Atta M, Dumas F, et al.: Production of the R2 subunit of ribon ucleotide reductase from herpes simplex virus with prokaryotic and eukaryotic expression systems: higher activity of R2 produced by eukaryotic cells related to higher iron-binding capacity. Biochemi J 1996;320:129–135.Google Scholar
  84. 84.
    Chabes A, Domkin V, Larsson G, Liu A, Graslund A, Wijmenga S, Thelander L: Yeast ribonucleotide reductase has a heterodimeric iron-radical-containing subunit. Proc Natl Acad Sci USA 2000;97:2474–2479.PubMedCrossRefGoogle Scholar
  85. 85.
    Romeo AM, Christen L, Niles EG, Kosman DJ: Intracellular chelation of iron by bipyridyl inhibits DNA virus replication: ribonucleotide reductase maturation as a probe of intracellular iron pools. J Biol Chem 2001;276:24301–24308.PubMedCrossRefGoogle Scholar
  86. 86.
    Boelaert JR, Weinberg GA, Weinberg ED: Altered iron metabolism in HIV infection: mechanisms, possible consequences, and proposals for management. Infect Agent Dis 1996;5:36–46.Google Scholar
  87. 87.
    Weinberg ED: Development of clinical methods of iron deprivation for suppression of neoplastic and infectious diseases. Cancer Invest 1999;17:507–513.PubMedGoogle Scholar
  88. 88.
    Fernandez-Pol JA, Hamilton PD, Klos DJ: Essential viral and cellular zinc and iron containing metalloproteins as targets for novel antiviral and anticancer agents: implications for prevention and therapy of viral diseases and cancer. Anticancer Res 2001;21:931–957.PubMedGoogle Scholar
  89. 89.
    Simonart T, Boelaert JR, Mosselmans R, Andrei G, Noel JC, De Clercq E, Snoeck R: Antiproliferative and apoptotic effects of iron chelators on human cervical carcinoma cells. Gynecol Oncol 2002;85:95–102.PubMedCrossRefGoogle Scholar
  90. 90.
    Dai Y, Gold B, Vishwanatha JK, Rhode SL: Mimosine inhibits viral DNA synthesis through ribonucleotide reductase. Virol 1994;205:210–216.CrossRefGoogle Scholar
  91. 91.
    Cinatl J, Jr., Cinatl J, Rabenau H, Gumbel HO, Kornhuber B, Doerr HW: In vitro inhibition of human cytomegalovirus replication by desferrioxamine. Antiviral Res 1994;25:73–77.PubMedCrossRefGoogle Scholar
  92. 92.
    Martelius T, Scholz M, Krogerus L, Hockerstedt K, Loginov R, Bruggeman C, et al.: Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection. Transplant 1999;68:1753–1761.CrossRefGoogle Scholar
  93. 93.
    Savarino A, Pescarmona GP, Boelaert JR: Iron metabolism and HIV infection: reciprocal interactions with potentially harmful consequences? Cell Biochem Funct 1999;17:279–287.PubMedCrossRefGoogle Scholar
  94. 94.
    Gordeuk VR, Delanghe JR, Langlois MR, Boelaert JR: Iron status and the outcome of HIV infection: an overview. J Clin Virol 2001;20:111–115.PubMedCrossRefGoogle Scholar
  95. 95.
    van Asbeck BS, Georgiou NA, van der Bruggen T, Oudshoorn M, Nottet HS, Marx JJ: Anti-HIV effect of iron chelators: different mechanisms involved. J Clin Virol 2001;20:141–147.PubMedCrossRefGoogle Scholar
  96. 96.
    Georgiou NA, van der Bruggen T, Oudshoorn M, Nottet HS, Marx JJ, van Asbeck BS: Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J Infect Dis 2000;181:484–490.PubMedCrossRefGoogle Scholar
  97. 97.
    Georgiou NA, van der Bruggen T, Oudshoorn M, Hider RC, Marx JJ, van Asbeck BS: Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis. Eur J Clin Invest 2002;32 Suppl 1:91–96.PubMedCrossRefGoogle Scholar
  98. 98.
    Sappey C, Boelaert JR, Legrand-Poels S, Forceille C, Favier A, Piette J: Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. AIDS Res Hum Retrovirus 1995;11:1049–1061.CrossRefGoogle Scholar
  99. 99.
    Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, et al.: Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 1995;22:449–456.PubMedCrossRefGoogle Scholar
  100. 100.
    Ikura Y, Morimoto H, Johmura H, Fukui M, Sakurai M: Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C. Am J Gastroenterol 1996;91:1367–1373.PubMedGoogle Scholar
  101. 101.
    Roeckel IE: Commentary: Iron metabolism in hepatitis C infection. Ann Clin Lab Sci 2000;30:163–165.PubMedGoogle Scholar
  102. 102.
    Fargion S, Fracanzani AL, Rossini A, Borzio M, Riggio O, Belloni G, et al.: Iron reduction and sustained response to interferon-alpha therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study. [comment]. Am J Gastroenterol 2002;97:1204–1210.PubMedGoogle Scholar
  103. 103.
    Piperno A, Vergani A, Malosio I, Parma L, Fossati L, Ricci A, et al.: Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations. Hepatology 1998;28:1105–1109.PubMedCrossRefGoogle Scholar
  104. 104.
    Bonkovsky HL: Iron as a comorbid factor in chronic viral hepatitis. [comment]. Am J Gastroenterol 2002;97:1–4.PubMedCrossRefGoogle Scholar
  105. 105.
    Martinelli AL, Franco RF, Villanova MG, Figueiredo JF, Secaf M, Tavella MH, et al.: Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection? Acta Haematol 2000;102:152–156.PubMedCrossRefGoogle Scholar
  106. 106.
    Bonkovsky HL, Troy N, McNeal K, Banner B, Sharma A, Obando J, et al.: Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C. Hepatol 2002;37:848–854.CrossRefGoogle Scholar
  107. 107.
    Diwakaran HH, Befeler AS, Britton RS, Brunt EM, Bacon BR: Accelerated hepatic fibrosis in patients with combined hereditary hemochromatosis and chronic hepatitis C infection. J Hepatol 2002;36:687–691.PubMedCrossRefGoogle Scholar
  108. 108.
    Tung BY, Emond MJ, Bronner MP, Raaka SD, Cotler SJ, Kowdley KV: Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology 2003;124:318–326.PubMedCrossRefGoogle Scholar
  109. 109.
    Van Vlierberghe H, Delanghe JR, De Bie S, Praet M, De Paepe A, Messiaen L, et al.: Association between Cys282Tyr missense mutation and haptoglobin phenotype polymorphism in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2001;13:1077–1081.PubMedCrossRefGoogle Scholar
  110. 110.
    Thorburn D, Curry G, Spooner R, Spence E, Oien K, Halls D, et al.: The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 2002;50:248–252.PubMedCrossRefGoogle Scholar
  111. 111.
    Tsuji Y, Kwak E, Saika T, Torti SV, Torti FM: Preferential repression of the H subunit of ferritin by adenovirus E1A in NIH-3T3 mouse fibroblasts. J Biol Chem 1993;268:7270–7275.PubMedGoogle Scholar
  112. 112.
    Tsuji Y, Akebi N, Lam TK, Nakabeppu Y, Torti SV, Torti FM: FER-1, an enhancer of the ferritin H gene and a target of EIA-mediated transcriptional repression. Mol Cell Biol 1995;15:5152–5164.PubMedGoogle Scholar
  113. 113.
    Tsuji Y, Moran E, Torti SV, Torti FM: Transcriptional regulation of the mouse ferritin H gene. Involvement of p300/CBP adaptor proteins in FER-1 enhancer activity. J Biol Chem 1999;274:7501–7507.PubMedCrossRefGoogle Scholar
  114. 114.
    Bevilacqua MA, Faniello MC, D’Agostino P, Quaresima B, Tiano MT, Pignata S, et al.: Transcriptional activation of the H-ferritin gene in differentiated Caco-2 cells parallels a change in the activity of the nuclear factor Bbf. Biochem J 1995;311:769–773.PubMedGoogle Scholar
  115. 115.
    Bevilacqua MA, Faniello MC, Quaresima B, Tiano MT, Giuliano P, Feliciello A, et al.: A common mechanism underlying the E1A repression and the cAMP stimulation of the H ferritin transcription. J Biol Chem 1997;272:20736–20741.PubMedCrossRefGoogle Scholar
  116. 116.
    Torti FM, Torti SV: Regulation of ferritin genes and protein. Blood 2002;99:3505–3516.PubMedCrossRefGoogle Scholar
  117. 117.
    Orino K, Tsuji Y, Torti FM, Torti SV: Adenovirus E1A blocks oxidant-dependent ferritin induction and sensitizes cells to pro-oxidant cytotoxicity. FEBS Lett 1999;461:334–338.PubMedCrossRefGoogle Scholar
  118. 118.
    Tsuji Y, Ayaki H, Whitman SP, Morrow CS, Torti SV, Torti FM: Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. Mol Cell Biol 2000;20:5818–5827.PubMedCrossRefGoogle Scholar
  119. 119.
    Ben-Arieh SV, Zimerman B, Smorodinsky NI, Yaacubovicz M, Schechter C, Bacik I, et al.: Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J Virol 2001;75:10557–10562.PubMedCrossRefGoogle Scholar
  120. 120.
    Vahdati-Ben Arieh S, Laham N, Schechter C, Yewdell JW, Coligan JE, Ehrlich R: A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules. Blood 2003;101:2858–2864.PubMedCrossRefGoogle Scholar
  121. 121.
    Jones TR, Hanson LK, Sun L, Slater JS, Stenberg RM, Campbell AE: Multiple independent loci within the human cytomegalovirus unique short region downregulate expression of major histocompatibility complex class I heavy chains. J Virol 1995;69:4830–4841.PubMedGoogle Scholar
  122. 122.
    Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL: The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 1996;84:769–779.PubMedCrossRefGoogle Scholar
  123. 123.
    Jones TR, Sun L: Human cytomegalovirus US2 destabilizes major histocompatibility complex class I heavy chains. J Virol 1997;71:2970–2979.PubMedGoogle Scholar
  124. 124.
    Machold RP, Wiertz EJ, Jones TR, Ploegh HL: The HCMV gene products US11 and US2 differ in their ability to attack allelic forms of murine major histocompatibility complex (MHC) class I heavy chains. J Exp Med 1997; 185:363–366.PubMedCrossRefGoogle Scholar
  125. 125.
    Farrell HE, Davis-Poynter NJ: From sabotage to camouflage: viral evasion of cytotoxic T lymphocyte and natural killer cell-mediated immunity. Sem Cell Develop Biol 1998;9:369–378.CrossRefGoogle Scholar
  126. 126.
    Mocarski ES, Jr.: Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trend Microbiol 2002;10:332–339.CrossRefGoogle Scholar
  127. 127.
    Vossen MT, Westerhout EM, Soderberg-Naucler C, Wiertz EJ: Viral immune evasion: a masterpiece of evolution. Immunogenetics 2002;54:527–542.PubMedCrossRefGoogle Scholar
  128. 128.
    Tomazin R, Boname J, Hegde NR, Lewinsohn DM, Altschuler Y, Jones TR, et al.: Cytomegalovius US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+T cells. Nat Med 1995;5:1039–1043.Google Scholar
  129. 129.
    Chevalier MS, Daniels GM, Johnson DC: Binding of human cytomegalovirus US2 to major histocompatibility complex class I and II proteins is not sufficient for their degradation. [Erratum appears in J Virol 2002 Dec; 76(24):13 126. J Virol 2002;76:8265–8275.PubMedCrossRefGoogle Scholar
  130. 130.
    Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, et al.: Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction [see comments]. Nature 1996;384:432–438.PubMedCrossRefGoogle Scholar
  131. 131.
    Gross CN, Irrinki A, Feder JN, Enns CA: Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation. J Biol Chem 1998;273:22068–22074.PubMedCrossRefGoogle Scholar
  132. 132.
    Corsi B, Levi S, Cozzi A, Corti A, Altimare D, Albertini A, Arosio P: Overexpression of the hereditary hemochromatosis protein, HFE, in HeLa cells induces and iron-deficient phenotype. FEBS Lett 1999;460: 149–152.PubMedCrossRefGoogle Scholar
  133. 133.
    Riedel HD, Muckenthaler MU, Gehrke SG, Mohr I, Brennan K, Hermann T, et al.: HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 1999;94:3915–3921.PubMedGoogle Scholar
  134. 134.
    Roy CN, Penny DM, Feder JN, Enns CA: The hereditary hemochromatosis protein. HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J Biol Chem 1999;274:9022–9028.PubMedCrossRefGoogle Scholar
  135. 135.
    Ramalingam TS, West AP, Jr., Lebron JA, Nangiana JS, Hogan TH, Enns CA, Bjorkman PJ: Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis. Nat Cell Biol 2000;2:953–957.PubMedCrossRefGoogle Scholar
  136. 136.
    Arredondo M, Munoz P, Mura CV, Nunez MT: HFE inhibits apical iron uptake by intestinal epithelial (Caco-2) cells. FASEB J 2001;15:1276–1278.PubMedGoogle Scholar
  137. 137.
    Feeney GP, Worwood M: The effects of wild-type and mutant HFE expression upon cellular iron uptake in transfected human embryonic kidney cells. Biochim Biophys Acta 2001;1538:242–251.PubMedCrossRefGoogle Scholar
  138. 138.
    Roy CN, Blemings KP, Deck KM, Davies PS, Anderson EL, Eisenstein RS, Enns CA: Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells. J Cell Physiol 2002;190:218–226.PubMedCrossRefGoogle Scholar
  139. 139.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al.: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis [see comments]. Nat Genet 1996;13:399–408.PubMedCrossRefGoogle Scholar
  140. 140.
    Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, et al.: The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem 1997;272:14025–14028.PubMedCrossRefGoogle Scholar
  141. 141.
    Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, Feder JN, et al.: Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997;94:12384–12389.PubMedCrossRefGoogle Scholar
  142. 142.
    Parkkila S, Waheed A, Britton RS, Bacon BR, Zhou XY, Tomatsu S, et al.: Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA 1997;94:13198–13202.PubMedCrossRefGoogle Scholar
  143. 143.
    Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, et al.: The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 1998;95:1472–1477.PubMedCrossRefGoogle Scholar
  144. 144.
    Salter-Cid L, Brunmark A, Li Y, Leturcq D, Peterson PA, Jackson MR, Yang Y: Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci USA 1999;96:5434–5439.PubMedCrossRefGoogle Scholar
  145. 145.
    Lebron JA, West AP, Jr, Bjorkman PJ: The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol 1999;294:239–245.PubMedCrossRefGoogle Scholar
  146. 146.
    Ikuta K, Fujimoto Y, Suzuki Y, Tanaka K, Saito H, Ohhira M, et al.: Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells. Biochim Biophys Acta 2000;1496:221–231.PubMedCrossRefGoogle Scholar
  147. 147.
    Kowdley KV, Tavill AS: At “ironic” case of mistaken identity? Hepatology 1992;16:500–501.PubMedCrossRefGoogle Scholar
  148. 148.
    Gerhard GS, Ten Elshof AE, Chorney MJ: Hereditary haemochromatosis as an immunological disease. Br J Haematol 1998;100:247–255.PubMedCrossRefGoogle Scholar
  149. 149.
    Pietrangelo A, Casalgrandi G, Quaglino D, Gualdi R, Conte D, Milani S, et al.: Duodenal ferritin synthesis in genetic hemochromatosis. Gastroenterology 1995;108:208–217.PubMedCrossRefGoogle Scholar
  150. 150.
    Simpson RJ, Debnam ES, Laftah AH, Solanky N, Beaumont NJ, Bahram S, et al.: Duodenal non-heme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out. Blood 2003;101:3316–3318.PubMedCrossRefGoogle Scholar
  151. 151.
    Trinder D, Olynyk JK, Sly WS, Morgan EH: Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Proc Natl Acad Sci USA 2002;99:5622–5626.PubMedCrossRefGoogle Scholar
  152. 152.
    Powell LW, Campbell CB, Wilson E: Intestinal mucosal uptake of iron and iron retention in idiopathic haemochromatosis as evidence for a mucosal abnormality. Gut 1970;11:727–731.PubMedGoogle Scholar
  153. 153.
    Bahram S, Gilfillan S, Kuhn LC, Moret R, Schulze JB, Lebeau A, Schumann K: Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc Natl Acad Sci USA 1999;96:13312–13317.PubMedCrossRefGoogle Scholar
  154. 154.
    Waheed A, Parkkila S, Saarnio J, Fleming RE, Zhou XY, Tomatsu S, et al.: Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci USA 1999;96:1579–1584.PubMedCrossRefGoogle Scholar
  155. 155.
    Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S: Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.[comment]. Proc Natl Acad Sci USA 2001;98:8780–8785.PubMedCrossRefGoogle Scholar
  156. 156.
    Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, et al.: Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002;99:4596–4601.PubMedCrossRefGoogle Scholar
  157. 157.
    Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al.: The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037–1044.PubMedCrossRefGoogle Scholar
  158. 158.
    Fletcher LM, Halliday JW: Haemochromatosis: understanding the mechanism of disease and implications for diagnosis and patient management following the recent cloning of novel genes involved in iron metabolism. J Intern Med 2002;251:181–192.PubMedCrossRefGoogle Scholar
  159. 159.
    Drakesmith H, Townsend A: The structure and function of HFE. Bioessays 2000;22:595–598.PubMedCrossRefGoogle Scholar
  160. 160.
    Montosi G, Paglia P, Garuti C, Guzman CA, Bastin JM, Colombo MP, Pietrangelo A: Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. Blood 2000;96:1125–1129.PubMedGoogle Scholar
  161. 161.
    Drakesmith H, Sweetland E, Schimanski L, Edwards J, Cowley D, Ashraf M, et al.: The hemochromatosis protein HFE inhibits iron export from macrophages. Proc Natl Acad Sci USA 2002;99:15602–15607.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Nihay Laham
    • 1
  • Rachel Ehrlich
    • 1
  1. 1.Department of Cell Research and Immunology, The George S. Wise Faculty of Life SciencesTel Aviv UniversityRamat AvivIsrael

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