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Iron and microbial infection

Nature Reviews Microbiology volume 2, pages 946–953 (2004)Cite this article

A Correction to this article was published on 01 March 2005

Key Points

  • Iron is an essential element for all living organisms, but is of low accessibility to both micro- and macroorganisms.

  • The competition between pathogens and their hosts for iron has shaped the evolution of both pathogen survival strategies in the host, as well as host microbicidal defence mechanisms.

  • In host defence, iron is involved in the production of reactive oxygen and nitrogen intermediates.

  • Iron uptake and metabolism in the mammalian host is a well-controlled system that involves various genes and molecules, including hepcidin, transferrin, the transferrin receptor, the divalent-metal transporter-1, ferroportin, natural resistance-associated macrophage protein-1 and ferritin, which are described in this review. Mutations in some of these genes lead to iron overload.

  • Pathogens have evolved to dwell in specific niches within the host/host cell and to access iron from host sources. For example, mycobacteria survive in the early endosomes of macrophages where they interact with the host iron-transfer system.

  • Iron overload favours certain infections, including tuberculosis in humans as well as in animal models. Iron overload supports the growth of mycobacteria and accelerates the development of tuberculosis in humans and mice.

  • Iron is also a modulator of both innate as well as acquired immunity.

  • In conclusion, studies that focus on the important role of iron in host–pathogen interactions should foster the development of new intervention strategies to improve global health.

Abstract

The use of iron as a cofactor in basic metabolic pathways is essential to both pathogenic microorganisms and their hosts. It is also a pivotal component of the innate immune response through its role in the generation of toxic oxygen and nitrogen intermediates. During evolution, the shared requirement of micro- and macroorganisms for this important nutrient has shaped the pathogen–host relationship. Here, we discuss how pathogens compete with the host for iron, and also how the host uses iron to counteract this threat.

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Figure 1: The niches of host-cell-associated microorganisms.
Figure 2: Iron metabolism in the host.
Figure 3: Iron metabolism and infection.

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References

  1. Hentze, M. W., Muckenthaler, M. U. & Andrews, N. C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117, 285–297 (2004). A comprehensive review of our current understanding of mammalian iron metabolism.

    Article  CAS  Google Scholar 

  2. Kaplan, J. Mechanisms of cellular iron acquisition: another iron in the fire. Cell 111, 603–606 (2002).

    Article  CAS  Google Scholar 

  3. Andrews, S. C., Robinson, A. K. & Rodriguez-Quinones, F. Bacterial iron homeostasis. FEMS Microbiol. Rev. 27, 215–237 (2003).

    Article  CAS  Google Scholar 

  4. Picard, V., Govoni, G., Jabado, N. & Gros, P. Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. J. Biol. Chem. 275, 35738–35745 (2000).

    Article  CAS  Google Scholar 

  5. Donovan, A. et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781 (2000).

    Article  CAS  Google Scholar 

  6. Ganz, T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102, 783–788 (2003).

    Article  CAS  Google Scholar 

  7. Gruenheid, S. et al. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med. 189, 831–841 (1999).

    Article  CAS  Google Scholar 

  8. Robson, K. J. et al. Recent advances in understanding haemochromatosis: a transition state. J. Med. Genet. 41, 721–730 (2004).

    Article  CAS  Google Scholar 

  9. Pietrangelo, A. Hereditary hemochromatosis—a new look at an old disease. N. Engl. J. Med. 350, 2383–2397 (2004).

    Article  CAS  Google Scholar 

  10. Eisenbach, C., Gehrke, S. G. & Stremmel, W. Iron, the HFE gene, and hepatitis C. Clin. Liver Dis. 8, 775–785 (2004).

    Article  Google Scholar 

  11. Bennett, M. J., Lebron, J. A. & Bjorkman, P. J. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403, 46–53 (2000).

    Article  CAS  Google Scholar 

  12. Enns, C. A. Pumping iron: the strange partnership of the hemochromatosis protein, a class I MHC homolog, with the transferrin receptor. Traffic 2, 167–174 (2001).

    Article  CAS  Google Scholar 

  13. Nicolas, G. et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nature Genet. 34, 97–101 (2003). This paper describes the essential function of hepcidin in iron metabolism.

    Article  CAS  Google Scholar 

  14. Canonne-Hergaux, F., Gruenheid, S., Govoni, G. & Gros, P. The Nramp1 protein and its role in resistance to infection and macrophage function. Proc. Assoc. Am. Physicians 111, 283–289 (1999).

    Article  CAS  Google Scholar 

  15. Hackam, D J. et al. Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J. Exp. Med. 188, 351–364 (1998).

    Article  CAS  Google Scholar 

  16. Jabado, N., Cuellar-Mata, P., Grinstein, S. & Gros, P. Iron chelators modulate the fusogenic properties of Salmonella-containing phagosomes. Proc. Natl Acad. Sci. USA 100, 6127–6132 (2003).

    Article  CAS  Google Scholar 

  17. Collins, H. L., Kaufmann, S. H. E. & Schaible, U. E. Iron chelation via deferoxamine exacerbates experimental salmonellosis via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase-dependent respiratory burst. J. Immunol. 168, 3458–3463 (2002).

    Article  CAS  Google Scholar 

  18. Mogues, T., Goodrich, M. E., Ryan, L., LaCourse, R. & North, R. J. The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J. Exp. Med. 193, 271–80 (2001)

    Article  CAS  Google Scholar 

  19. Posey, J. E. & Gherardini, F. C. Lack of a role for iron in the Lyme disease pathogen. Science 288, 1651–1653 (2000). This work describes the unusual case of a bacterial pathogen, which does not require iron.

    Article  CAS  Google Scholar 

  20. Weinberg, E. D. Iron and infection. Microbiol. Rev. 42, 45–66 (1978)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ratledge, C. & Dover, L. G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000). A comprehensive review on our current knowledge of bacterial iron uptake systems.

    Article  CAS  Google Scholar 

  22. Ratledge, C. Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb.) 84, 110–130 (2004).

    Article  Google Scholar 

  23. Brown, J. S. & Holden, D. W. Iron acquisition by Gram-positive bacterial pathogens. Microbes Infect. 4, 1149–1156 (2002).

    Article  CAS  Google Scholar 

  24. Agranoff, D. D. & Krishna, S. Metal ion homeostasis and intracellular parasitism. Mol. Microbiol. 28, 403–412 (1998).

    Article  CAS  Google Scholar 

  25. Rodriguez, G. M. & Smith, I. Mechanisms of iron regulation in mycobacteria: role in physiology and virulence. Mol. Microbiol. 47, 1485–1494 (2003).

    Article  CAS  Google Scholar 

  26. Manabe, Y. C., Saviola, B. J., Sun, L., Murphy, J. R. & Bishai, W. R. Attenuation of virulence in Mycobacterium tuberculosis expressing a constitutively active iron repressor. Proc. Natl Acad. Sci. USA 96, 12844–12848 (1999).

    Article  CAS  Google Scholar 

  27. Gold, B., Rodriguez, G. M., Marras, S. A., Pentecost, M. & Smith, I. The Mycobacterium tuberculosis IdeR is a dual functional regulator that controls transcription of genes involved in iron acquisition, iron storage and survival in macrophages. Mol. Microbiol. 42, 851–865 (2001).

    Article  CAS  Google Scholar 

  28. Skaar, E. P., Humayun, M., Bae, T., DeBord, K. L. & Schneewind, O. Iron-source preference of Staphylococcus aureus infections. Science 305, 1626–1628 (2004). This paper demonstrates that haem-bound iron is the main iron source for staphylococci.

    Article  CAS  Google Scholar 

  29. Al Younes, H. M., Rudel, T., Brinkmann, V., Szczepek, A. J. & Meyer, T. F. Low iron availability modulates the course of Chlamydia pneumoniae infection. Cell. Microbiol. 3, 427–437 (2001).

    Article  CAS  Google Scholar 

  30. Byrd, T. F. & Horwitz, M. A. Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon ã-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. 88, 1103–1112 (1991).

    Article  CAS  Google Scholar 

  31. Olakanmi, O., Britigan, B. E. & Schlesinger, L. S. Gallium disrupts iron metabolism of mycobacteria residing within human macrophages. Infect. Immun. 68, 5619–5627 (2000).

    Article  CAS  Google Scholar 

  32. Schaible, U. E., Collins, H. L., Priem, F. & Kaufmann, S. H. E. Correction of the iron overload defect in β-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J. Exp. Med. 196, 1507–1513 (2002). Shows that, in an animal model, iron overload accelerates tuberculosis and that lactoferrin can be used to correct this effect.

    Article  CAS  Google Scholar 

  33. Lounis, N., Truffot-Pernot, C., Grosset, J., Gordeuk, V. R. & Boelaert, J. R. Iron and Mycobacterium tuberculosis infection. J. Clin. Virol. 20, 123–126 (2001).

    Article  CAS  Google Scholar 

  34. Schaible, U., Collins, H. & Kaufmann, S. H. E. Confrontation between intracellular bacteria and the immune system. Adv. Immunol. 71, 267–377 (1999).

    Article  CAS  Google Scholar 

  35. Olakanmi, O., Schlesinger, L. S., Ahmed, A. & Britigan, B. E. Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-ã and hemochromatosis. J. Biol. Chem. 277, 49727–49734 (2002).

    Article  CAS  Google Scholar 

  36. Bockmann, R., Dickneite, C., Middendorf, B., Goebel, W. & Sokolovic, Z. Specific binding of the Listeria monocytogenes transcriptional regulator PrfA to target sequences requires additional factor(s) and is influenced by iron. Mol. Microbiol. 22, 643–653 (1996).

    Article  CAS  Google Scholar 

  37. Deneer, H. G, Healey, V. & Boychuk, I. Reduction of exogenous ferric iron by a surface-associated ferric reductase of Listeria spp. Microbiology 141, 1985–1992 (1995).

    Article  CAS  Google Scholar 

  38. Larson, J. A., Howie, H. L. & So, M. Neisseria meningitidis accelerates ferritin degradation in host epithelial cells to yield an essential iron source. Mol. Microbiol. 53, 807–820 (2004). This paper identifies meningococci as the first pathogens to use ferritin as a host-derived iron source.

    Article  CAS  Google Scholar 

  39. Schaible, U. E., Sturgill-Koszycki, S., Schlesinger, P. H. & Russell, D. G. Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages. J. Immunol. 160, 1290–1296 (1998).

    CAS  PubMed  Google Scholar 

  40. Byrd, T. F. & Horwitz, M. A. Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon γ. J. Clin. Invest. 91, 969–976 (1993).

    Article  CAS  Google Scholar 

  41. Timm, J. et al. Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients. Proc. Natl Acad. Sci. USA 100, 14321–14326 (2003).

    Article  CAS  Google Scholar 

  42. Moalem, S., Weinberg, E. D. & Percy, M. E. Hemochromatosis and the enigma of misplaced iron: implications for infectious disease and survival. Biometals 17, 135–139 (2004).

    Article  CAS  Google Scholar 

  43. Murray, M. J., Murray, A. B., Murray, M. B. & Murray, C. J. The adverse effect of iron repletion on the course of certain infections. Br. Med. J. 2, 1113–1115 (1978).

    Article  CAS  Google Scholar 

  44. Weinberg, E. D. Iron loading and disease surveillance. Emerg. Infect. Dis. 5, 346–352 (1999).

    Article  CAS  Google Scholar 

  45. Trousseau, A. True and false chlorosis. Lectures on Clinical Medicine 5, 95–117 (1872).

    Google Scholar 

  46. Gordeuk, V. R. African iron overload. Semin. Hematol. 39, 263–269 (2002).

    Article  CAS  Google Scholar 

  47. Gangaidzo, I. T. et al. Association of pulmonary tuberculosis with increased dietary iron. J. Infect. Dis. 184, 936–939 (2001). This article demonstrates the epidemiological correlation between iron overload and the risk of tuberculosis in a human population.

    Article  CAS  Google Scholar 

  48. Gordeuk, V. R., McLaren, C. E., MacPhail, A. P., Deichsel, G. & Bothwell, T. H. Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited. Blood 87, 3470–3476 (1996).

    CAS  PubMed  Google Scholar 

  49. Gordeuk, V. et al. Iron overload in Africa. Interaction between a gene and dietary iron content. N. Engl. J. Med. 326, 95–100 (1992).

    Article  CAS  Google Scholar 

  50. Santos, M., Clevers, H., De Sousa, M. & Marx, J. J. Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in β2-microglobulin knockout mice. Blood 91, 3059–3065 (1998).

    CAS  PubMed  Google Scholar 

  51. Rolph, M. S. et al. MHC class Ia-restricted T cells partially account for β2-microglobulin-dependent resistance to Mycobacterium tuberculosis. Eur. J. Immunol. 31, 1944–1949 (2001).

    Article  CAS  Google Scholar 

  52. Behar, S. M., Dascher, C. C., Grusby, M. J., Wang, C. R. & Brenner, M. B. Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J. Exp. Med. 189, 1973–1980 (1999).

    Article  CAS  Google Scholar 

  53. Bartfay, W. J. & Bartfay, E. Systemic oxygen-free radical production in iron-loaded mice. West. J. Nurs. Res. 22, 927–935 (2000).

    Article  CAS  Google Scholar 

  54. Alford, C. E., King, T. E. Jr & Campbell, P. A. Role of transferrin, transferrin receptors, and iron in macrophage listericidal activity. J. Exp. Med. 174, 459–466 (1991).

    Article  CAS  Google Scholar 

  55. Ward, P. P., Uribe-Luna, S. & Conneely, O. M. Lactoferrin and host defense. Biochem. Cell Biol. 80, 95–102 (2002).

    Article  CAS  Google Scholar 

  56. Vorland, L. H. Lactoferrin: a multifunctional glycoprotein. APMIS 107, 971–981 (1999).

    Article  CAS  Google Scholar 

  57. Singh, P. K., Parsek, M. R., Greenberg, E. P. & Welsh, M. J. A component of innate immunity prevents bacterial biofilm development. Nature 417, 552–555 (2002). This study reveals the importance of lactoferrin in innate immunity.

    Article  CAS  Google Scholar 

  58. Griffiths, E. A. et al. In vivo effects of bifidobacteria and lactoferrin on gut endotoxin concentration and mucosal immunity in Balb/c mice. Dig. Dis. Sci. 49, 579–589 (2004).

    Article  CAS  Google Scholar 

  59. Tanida, T., Rao, F., Hamada, T., Ueta, E. & Osaki, T. Lactoferrin peptide increases the survival of Candida albicans-inoculated mice by upregulating neutrophil and macrophage functions, especially in combination with amphotericin B and granulocyte-macrophage colony-stimulating factor. Infect. Immun. 69, 3883–3890 (2001).

    Article  CAS  Google Scholar 

  60. Ueta, E., Tanida, T., & Osaki, T. A novel bovine lactoferrin peptide, FKCRRWQWRM, suppresses Candida cell growth and activates neutrophils. J. Pept. Res. 57, 240–249 (2001).

    Article  CAS  Google Scholar 

  61. Tanida, T., Rao, F., Hamada, T., Ueta, E. & Osaki, T. Lactoferrin peptide increases the survival of Candida albicans-inoculated mice by upregulating neutrophil and macrophage functions, especially in combination with amphotericin B and granulocyte-macrophage colony-stimulating factor. Infect. Immun. 69, 3883–3890 (2001).

    Article  CAS  Google Scholar 

  62. Yamauchi, K., Tomita, M., Giehl, T. J. & Ellison, R. T. Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect. Immun. 61, 719–728 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Walker, E. M. Jr & Walker, S. M. Effects of iron overload on the immune system. Ann. Clin. Lab. Sci. 30, 354–365 (2000).

    CAS  PubMed  Google Scholar 

  64. Kuvibidila, S. R. & Porretta, C. Iron deficiency and in vitro iron chelation reduce the expression of cluster of differentiation molecule (CD)28 but not CD3 receptors on murine thymocytes and spleen cells. Br. J. Nutr. 90, 179–189 (2003).

    Article  CAS  Google Scholar 

  65. Grant, S. M., Wiesinger, J. A., Beard, J. L. & Cantorna, M. T. Iron-deficient mice fail to develop autoimmune encephalomyelitis. J. Nutr. 133, 2635–2638 (2003).

    Article  CAS  Google Scholar 

  66. Omara, F. O. & Blakley, B. R. The IgM and IgG antibody responses in iron-deficient and iron-loaded mice. Biol. Trace Elem. Res. 46, 155–161 (1994).

    Article  CAS  Google Scholar 

  67. Omara, F. O. & Blakley, B. R. The effects of iron deficiency and iron overload on cell-mediated immunity in the mouse. Br. J. Nutr. 72, 899–909 (1994).

    Article  CAS  Google Scholar 

  68. Cunningham-Rundles, S. et al. Effect of transfusional iron overload on immune response. J. Infect. Dis. 182, S115–S121 (2000).

    Article  CAS  Google Scholar 

  69. Wanachiwanawin, W. Infections in ε-β-thalassemia. J. Pediatr. Hematol. Oncol. 22, 581–587 (2000).

    Article  CAS  Google Scholar 

  70. de Sousa, M. & Porto, G. The immunological system in hemochromatosis. J. Hepatol. 28, (Suppl. 1) 1–7 (1998).

    Article  Google Scholar 

  71. Bisti, S. et al. The outcome of Leishmania major experimental infection in BALB/c mice can be modulated by exogenously delivered iron. Eur. J. Immunol. 30, 3732–3740 (2000).

    Article  CAS  Google Scholar 

  72. Weiss, G. et al. Associations between cellular immune effector function, iron metabolism, and disease activity in patients with chronic hepatitis C virus infection. J. Infect. Dis. 180, 1452–1458 (1999).

    Article  CAS  Google Scholar 

  73. Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271–1276 (2004). This paper elucidates an important link between innate immunity and regulation of iron metabolism.

    Article  CAS  Google Scholar 

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Acknowledgements

Financial support was provided to S.H.E.K and U.E.S. by the Deutsche Forschungsgemeinschaft.The authors thank L. Fehlig for wonderful help with the figures and J. Koth for expert secretarial assistance.

Author information

Authors and Affiliations

  1. Department of Immunology, Max-Planck-Institute for Infection Biology, Schumannstrasse 21-22, Berlin, D-10117, Germany

    Ulrich E. Schaible & Stefan H. E. Kaufmann

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  1. Ulrich E. Schaible
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Correspondence to Stefan H. E. Kaufmann.

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DATABASES

Entrez

bfrA

ferroportin-1

HFE

Nramp1

SwissProt

CD163

DCYTB

DMT1

FepA

FepB

ferroportin

IdeR

TFR2

TonB

FURTHER INFORMATION

Stefan H. E. Kaufmann's laboratory

Glossary

DEFENSINS

Small basic peptides produced by immune cells that mediate their microbicidal effects by damaging bacterial membranes.

β-2-MICROGLOBULIN

(β2m). A 12-kDa protein that is non-covalently associated with MHC class-I molecules and their homologues — CD1 and HFE.

EARLY ENDOSOME

Early stage of an intracellular vesicle after endocytosis, characterized by the presence of the transferrin receptor and a mildly acidic pH.

LATE ENDOSOME

Later stage of the endosome, characterized by the presence of hydrolytic enzymes and an acidic pH.

SIDEROPHORES

Low-molecular-weight molecules that sequester extracellular iron for bacterial uptake.

LYME DISEASE

A disease transmitted by ticks that presents with inflammation in the skin, joints heart and/or nervous system.

ABC-TRANSPORTER

Member of a membrane-spanning transporter protein family that contains an ATP-binding cassette.

TRANSCRIPTOME ANALYSIS

Analysis of the global gene expression of a cell by identification of all the messenger RNA present in the cell.

NATURAL KILLER (NK) T CELLS

A small subset of T cells that express markers of both NKcells and T cells. They express a T-cell receptor of limited diversity and are restricted by CD1d.

BIOFILM

A dense layer of bacteria in which the bacterial cells are enclosed by an extracellular matrix.

CYSTIC FIBROSIS

An autosomal recessive disease characterized by pulmonary pathology and dysfunction of exocrine glands.

CYTOKINES

Biologically active molecules that are released by cells (mainly leukocytes) and that modulate the function of other cells by binding to specific receptors.

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Schaible, U., Kaufmann, S. Iron and microbial infection. Nat Rev Microbiol 2, 946–953 (2004). https://doi.org/10.1038/nrmicro1046

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