Indian Journal of Microbiology

, Volume 58, Issue 3, pp 257–267 | Cite as

The ‘Checkmate’ for Iron Between Human Host and Invading Bacteria: Chess Game Analogy

  • V. Kalidasan
  • Narcisse Joseph
  • Suresh Kumar
  • Rukman Awang Hamat
  • Vasantha Kumari Neela
Review Article


Iron is an essential nutrient for all living organisms with critical roles in many biological processes. The mammalian host maintains the iron requirements by dietary intake, while the invading pathogenic bacteria compete with the host to obtain those absorbed irons. In order to limit the iron uptake by the bacteria, the human host employs numerous iron binding proteins and withholding defense mechanisms that capture iron from the microbial invaders. To counteract, the bacteria cope with the iron limitation imposed by the host by expressing various iron acquisition systems, allowing them to achieve effective iron homeostasis. The armamentarium used by the human host and invading bacteria, leads to the dilemma of who wins the ultimate war for iron.


Iron Host–pathogen Iron homeostasis Host defense Siderophore Microbial iron acquisition 



This work was supported by Ministry of Higher Education, Malaysia through Fundamental Research Grant Scheme [04-01-14-53FR] and Universiti Putra Malaysia through Geran Putra—Inisiatif Putra Siswazah (IPS) [GP-IPS/2016/9478200].

Compliance of Ethical Standards

Conflicts of interest

The authors declare that they have no competing interests.


  1. 1.
    DiGuiseppi J, Fridovich I (1982) Oxygen toxicity in Streptococcus sanguis. J Biol Chem 257:4046–4051PubMedGoogle Scholar
  2. 2.
    Archibald F (1983) Lactobacillus plantarum, an organism not requiring iron. FEMS Microbiol Lett 19:29–32. CrossRefGoogle Scholar
  3. 3.
    Posey JE, Gherardini FC (2000) Lack of role for iron in lyme disease pathogen. Science (80) 288:1651–1653.
  4. 4.
    Posey JE, Hardham JM, Norris SJ, Gherardini FC (1999) Characterization of a manganese-dependent regulatory protein, TroR, from Treponema pallidum. Proc Natl Acad Sci USA 96:10887–10892. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chen L, Zheng D, Liu B et al (2016) VFDB 2016: hierarchical and refined dataset for big data analysis—10 years on. Nucleic Acids Res 44:D694–D697. CrossRefPubMedGoogle Scholar
  6. 6.
    Symeonidis A, Marangos M (2012) Iron and microbial growth. In: Insight and control of Infectious disease in global scenario. InTech, pp. 289–330.
  7. 7.
    Von Drygalski A, Adamson JW (2013) Iron metabolism in man. J Parenter Enter Nutr 37:599–606. CrossRefGoogle Scholar
  8. 8.
    Andrews NC, Schmidt PJ (2007) Iron homeostasis. Annu Rev Physiol 69:69–85. CrossRefPubMedGoogle Scholar
  9. 9.
    Schaible UE, Kaufmann SH (2004) Iron and microbial infection. Nat Rev Microbiol 2:946–953. CrossRefPubMedGoogle Scholar
  10. 10.
    Messenger AJ, Barclay R (1983) Bacteria, iron and pathogenicity. Biochem Educ 11:54–63. CrossRefGoogle Scholar
  11. 11.
    Andrews SC, Robinson AK, Rodríguez-Quiñones F (2003) Bacterial iron homeostasis. FEMS Microbiol Rev 27:215–237. CrossRefPubMedGoogle Scholar
  12. 12.
    Cornelis P, Wei Q, Andrews SC, Vinckx T (2011) Iron homeostasis and management of oxidative stress response in bacteria. Metallomics 3:540–549. CrossRefPubMedGoogle Scholar
  13. 13.
    Wandersman C, Delepelaire P (2004) Bacterial iron sources: from siderophores to hemophores. Annu Rev Microbiol 58:611–647. CrossRefPubMedGoogle Scholar
  14. 14.
    Hennigar SR, McClung JP (2016) Nutritional immunity: starving pathogens of trace minerals. Am J Lifestyle Med. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Indriati Hood M, Skaar EP (2012) Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol. PubMedCrossRefGoogle Scholar
  16. 16.
    McLaren GD, Muir WA, Kellermeyer RW, Jacobs A (1983) Iron overload disorders: natural history, pathogenesis, diagnosis, and therapy. CRC Crit Rev Clin Lab Sci 19:205–266. CrossRefGoogle Scholar
  17. 17.
    Khan FA, Fisher MA, Khakoo RA (2007) Association of hemochromatosis with infectious diseases: expanding spectrum. Int J Infect Dis 11:482–487. CrossRefPubMedGoogle Scholar
  18. 18.
    Gangaidzo IT, Moyo VM, Mvundura E et al (2001) Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis 184:936–939. CrossRefPubMedGoogle Scholar
  19. 19.
    Canziani MEF, Yumiya ST, Rangel EB et al (2001) Risk of bacterial infection in patients under intravenous iron therapy: dose versus length of treatment. Artif Organs 25:866–869. CrossRefPubMedGoogle Scholar
  20. 20.
    Maynor L, Brophy DF (2007) Risk of infection with intravenous iron therapy. Ann Pharmacother 41:1476–1480. CrossRefPubMedGoogle Scholar
  21. 21.
    Taylor RW, Manganaro L, O’Brien J et al (2002) Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient. Crit Care Med 30:2249–2254. CrossRefPubMedGoogle Scholar
  22. 22.
    Palmer KT, Poole J, Ayres JG et al (2003) Exposure to metal fume and infectious pneumonia. Am J Epidemiol 157:227–233. CrossRefPubMedGoogle Scholar
  23. 23.
    Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta—Gen Subj 1790:600–605. CrossRefGoogle Scholar
  24. 24.
    Kumar V, Choudhry VP (2010) Iron deficiency and infections. Indian J Pediatr 77:789–793CrossRefPubMedGoogle Scholar
  25. 25.
    Chung MC-M (1984) Structure and function of transferrin. Biochem Educ 12:146–154. CrossRefGoogle Scholar
  26. 26.
    Otto BR, Verweij-van Vught AM, MacLaren DM (1992) Transferrins and heme-compounds as iron sources for pathogenic bacteria. Crit Rev Microbiol 18:217–233. CrossRefPubMedGoogle Scholar
  27. 27.
    Thorstensen K, Romslo I (1990) The role of transferrin in the mechanism of cellular iron uptake. Biochem J 271:1–9CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Farnaud S, Evans RW (2003) Lactoferrin—a multifunctional protein with antimicrobial properties. Mol Immunol 40:395–405. CrossRefPubMedGoogle Scholar
  29. 29.
    Ward PP, Conneely OM (2004) Lactoferrin: role in iron homeostasis and host defense against microbial infection. Biometals 17:203–208. CrossRefPubMedGoogle Scholar
  30. 30.
    Ward PP, Paz E, Conneely OM (2005) Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 62:2540–2548. CrossRefPubMedGoogle Scholar
  31. 31.
    Vorland LH (1999) Lactoferrin: a multifmctional glycoprotein. Acta Pathol Microbiol Immunol Scand 107:971–981CrossRefGoogle Scholar
  32. 32.
    Orino K, Watanabe K (2008) Molecular, physiological and clinical aspects of the iron storage protein ferritin. Vet J 178:191–201. CrossRefPubMedGoogle Scholar
  33. 33.
    Reif DW (1992) Ferritin as a source of iron for oxidative damage. Free Radic Biol Med 12:417–427. CrossRefPubMedGoogle Scholar
  34. 34.
    Arosio P, Levi S (2002) Ferritin, iron homeostasis, and oxidative damage. Free Radic Biol Med 33:457–463. CrossRefPubMedGoogle Scholar
  35. 35.
    Arosio P, Ingrassia R, Cavadini P (2009) Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta 1790:589–599. CrossRefPubMedGoogle Scholar
  36. 36.
    Theil EC (2003) Ferritin: at the crossroads of iron and oxygen metabolism. J Nutr 133:1549–1553CrossRefGoogle Scholar
  37. 37.
    Carrondo MA (2003) Ferritins, iron uptake and storage from the bacterioferritin viewpoint. EMBO J 22:1959–1968. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Anzaldi LL, Skaar EP (2010) Overcoming the heme paradox: heme toxicity and tolerance in bacterial pathogens. Infect Immun 78:4977–4989. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Tong Y, Guo M (2009) Bacterial heme-transport proteins and their heme-coordination modes. Arch Biochem Biophys 481:1–15. CrossRefPubMedGoogle Scholar
  40. 40.
    Pieracci FM, Barie PS (2005) Iron and the risk of infection. Surg Infect (Larchmt) 6:41–46. CrossRefGoogle Scholar
  41. 41.
    Parrow NL, Fleming RE, Minnick MF (2013) Sequestration and scavenging of iron in infection. Infect Immun 81:3503–3514. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Saha R, Saha N, Donofrio RS, Bestervelt LL (2013) Review microbial siderophores: a mini review. J Basic Microbiol 53:303–317. CrossRefPubMedGoogle Scholar
  43. 43.
    Miethke M, Marahiel MA (2007) Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 71:413–451. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hotta K, Kim CY, Fox DT, Koppisch AT (2010) Siderophore-mediated iron acquisition in Bacillus anthracis and related strains. Microbiology 156:1918–1925. CrossRefPubMedGoogle Scholar
  45. 45.
    Cornelis P, Dingemans J (2013) Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections. Front Cell Infect Microbiol 3:75. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Skaar EP (2010) The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathog 6:1–2. CrossRefGoogle Scholar
  47. 47.
    Evans RW, Oakhill JS (2002) Transferrin-mediated iron acquisition by pathogenic Neisseria. Biochem Soc 30:705–707. CrossRefGoogle Scholar
  48. 48.
    Noinaj N, Easley NC, Oke M et al (2012) Structural basis for iron piracy by pathogenic Neisseria. Nature 483:53–58. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Genco CA, Desai PJ (1996) Iron acquisition in the pathogenic Neisseria. Trends Microbiol 4:179–184. CrossRefPubMedGoogle Scholar
  50. 50.
    Schryvers AB, Stojiljkovic I (1999) Iron acquisition systems in the pathogenic Neisseria. Mol Microbiol 32:1117–1123. CrossRefPubMedGoogle Scholar
  51. 51.
    Gray-Owen SD, Loosmore S, Schryvers AB (1995) Identification and characterization of genes encoding the human transferrin-binding proteins from Haemophilus influenzae. Infect Immun 63:1201–1210PubMedPubMedCentralGoogle Scholar
  52. 52.
    Loosmore SM, Yang YP, Coleman DC et al (1996) Cloning and expression of the Haemophilus influenzae transferrin receptor genes. Mol Microbiol 19:575–586CrossRefPubMedGoogle Scholar
  53. 53.
    Herrington DA, Sparling PF (1985) Haemophilus influenzae can use human transferrin as a sole source for required iron. Infect Immun 48:248–251PubMedPubMedCentralGoogle Scholar
  54. 54.
    Gonzalez GC, Caamano DL, Schryvers AB (1990) Identification and characterization of a porcine-specific transferrin receptor in Actinobacillus pleuropneumoniae. Mol Microbiol 4:1173–1179. CrossRefPubMedGoogle Scholar
  55. 55.
    Perkins-Balding D, Ratliff-Griffin M, Stojiljkovic I (2004) Iron transport systems in Neisseria meningitidis. Microbiol Mol Biol Rev 68:154–171. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Criado MT, Pintor M, Ferreirós CM (1993) Iron uptake by Neisseria meningitidis. Res Microbiol 144:77–82. CrossRefPubMedGoogle Scholar
  57. 57.
    Rohde KH, Dyer DW (2003) Mechanisms of iron acquisition by the human pathogens Neisseria Meningitidis and Neisseria Gonorrhoeae. Front Biosci 8:1186–1218. CrossRefGoogle Scholar
  58. 58.
    Ganz T (2009) Iron in innate immunity: starve the invaders. Curr Opin Immunol 21:63–67. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Wyllie S, Seu P, Goss JA (2002) The natural resistance-associated macrophage protein 1 Slc11a1 (formerly Nramp1) and iron metabolism in macrophages. Microbes Infect 4:351–359. CrossRefPubMedGoogle Scholar
  60. 60.
    Cellier MF, Courville P, Campion C (2007) Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect 9:1662–1670. CrossRefPubMedGoogle Scholar
  61. 61.
    Govoni G, Gros P (1998) Macrophage NRAMP1 and its role in resistance to microbial infections. Inflamm Res 47:277–284. CrossRefPubMedGoogle Scholar
  62. 62.
    Ganz T, Nemeth E (2012) Hepcidin and iron homeostasis. Biochim Biophys Acta—Mol Cell Res 1823:1434–1443. CrossRefGoogle Scholar
  63. 63.
    Rishi G, Wallace DF, Subramaniam VN (2015) Hepcidin: regulation of the master iron regulator. Biosci Rep 35:e00192. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Rossi E (2005) Hepcidin–the iron regulatory hormone. Clin Biochem Rev 26:47–49PubMedPubMedCentralGoogle Scholar
  65. 65.
    Collins JF, Wessling-Resnick M, Knutson MD (2008) Hepcidin regulation of iron transport. J Nutr 138:2284–2288. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bullen JJ, Rogers HJ, Spalding PB, Ward CG (2006) Natural resistance, iron and infection: a challenge for clinical medicine. J Med Microbiol 55:251–258. CrossRefPubMedGoogle Scholar
  67. 67.
    Boelaert JR, Vandecasteele SJ, Appelberg R, Gordeuk VR (2007) The effect of the host’s iron status on tuberculosis. J Infect Dis 195:1745–1753. CrossRefPubMedGoogle Scholar
  68. 68.
    Lounis N, Truffot-Pernot C, Grosset J et al (2001) Iron and Mycobacterium tuberculosis infection. J Clin Virol 20:123–126. CrossRefPubMedGoogle Scholar
  69. 69.
    Sritharan M (2000) Iron as a candidate in virulence and pathogenesis in mycobacteria and other microorganisms. World J Microbiol Biotechnol 16:769–780. CrossRefGoogle Scholar
  70. 70.
    Pandey R, Rodriguez GM (2014) IdeR is required for iron homeostasis and virulence in Mycobacterium tuberculosis. Mol Microbiol 91:98–109. CrossRefPubMedGoogle Scholar
  71. 71.
    Sow FB, Nandakumar S, Velu V et al (2011) Mycobacterium tuberculosis components stimulate production of the antimicrobial peptide hepcidin. Tuberculosis 91:314–321. CrossRefPubMedGoogle Scholar
  72. 72.
    Sow FB, Florence WC, Satoskar AR et al (2007) Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 82:934–945. CrossRefPubMedGoogle Scholar
  73. 73.
    North RJ, Lacourse R, Ryan L et al (1999) Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice. Infect Immun 67:5811–5814PubMedPubMedCentralGoogle Scholar
  74. 74.
    Prentice AM (2008) Iron metabolism, malaria, and other infections: what is all the fuss about? Symp A Q J Mod Foreign Lit. CrossRefGoogle Scholar
  75. 75.
    Prentice AM, Ghattas H, Doherty C, Cox SE (2007) Iron metabolism and malaria. Food Nutr Bull 28:524–539. CrossRefGoogle Scholar
  76. 76.
    Sazawal S, Black R, Ramsan M et al (2006) Effect of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community based, randomised, placebo-controlled trial. Lancet 367:133–143. CrossRefPubMedGoogle Scholar
  77. 77.
    Spottiswoode N, Duffy PE, Drakesmith H (2014) Iron, anemia and hepcidin in malaria. Front Pharmacol 5:1–12. CrossRefGoogle Scholar
  78. 78.
    Armitage AE, Pinches R, Eddowes LA et al (2009) Plasmodium falciparum infected erythrocytes induce hepcidin (HAMP) mRNA synthesis by peripheral blood mononuclear cells. Br J Haematol 147:769–771. CrossRefPubMedGoogle Scholar
  79. 79.
    Prentice AM (2011) Hepcidin and iron-mediated resistance to malaria. EMBO Mol Med 3:620–622. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Wang H-Z, He Y-X, Yang C-J et al (2011) Hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection. J Immunol 187:6410–6416. CrossRefPubMedGoogle Scholar
  81. 81.
    Spottiswoode N, Armitage AE, Williams AR et al (2017) Role of activins in hepcidin regulation during malaria. Infect Immun 85:1–17. CrossRefGoogle Scholar
  82. 82.
    Banjoko SO, Oseni FA, Togun RA et al (2012) Iron status in HIV-1 infection: implications in disease pathology. BMC Clin Pathol 12:1. CrossRefGoogle Scholar
  83. 83.
    Manafa PO, Aneke JC, Okocha CE et al (2017) The human immunodeficiency virus infection is associated with positive iron balance among subjects in Nnewi, South East Nigeria. J HIV Hum Reprod 4:8–12Google Scholar
  84. 84.
    Gordeuk VR, Delanghe JR, Langlois MR, Boelaert JR (2001) Iron status and the outcome of HIV infection: an overview. J Clin Virol 20:111–115. CrossRefPubMedGoogle Scholar
  85. 85.
    Xu M, Kashanchi F, Foster A et al (2010) Hepcidin induces HIV-1 transcription inhibited by ferroportin. Retrovirology. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Nekhai S, Kumari N, Dhawan S (2013) Role of cellular iron and oxygen in the regulation of HIV-1 infection. Future Virol 8:301–311. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Chang H-C, Bayeva M, Taiwo B et al (2015) High cellular iron levels are associated with increased HIV infection and replication. AIDS Res Hum Retroviruses 31:305–312. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Association of Microbiologists of India 2018

Authors and Affiliations

  1. 1.Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health SciencesUniversiti Putra Malaysia (43400 UPM)SerdangMalaysia

Personalised recommendations