Iron in intracellular infection: To provide or to deprive?

Frontiers in Cellular and Infection Microbiology

Volumn 3, Issue DEC, 2013, Pages

  Silva Gomes, Sandro ^a,b   Vale Costa, Sílvia ^a,b   Appelberg, Rui ^a,b   Gomes, Maria S ^a,b  

^a UNIVERSITY OF PORTO   (Portugal)

^b UNIVERSITY OF PORTO   (Portugal)

Author keywords

Immunity; Infection; Leishmania; Mycobacterium; Transition metal

Indexed keywords

CD71 ANTIGEN; DEFEROXAMINE; FERROPORTIN; GAMMA INTERFERON; HEPCIDIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 10; INTERLEUKIN 4; IRON; LIPOCALIN; TRANSFERRIN; TRANSITION ELEMENT;

CANINE MODEL; HOST PATHOGEN INTERACTION; HUMAN; INFECTION; INTRACELLULAR INFECTION; IRON DEFICIENCY; IRON METABOLISM; IRON OVERLOAD; LEISHMANIASIS; MYCOBACTERIOSIS; NONHUMAN; REVIEW; RODENT MODEL; CYTOSOL; HOMEOSTASIS; IMMUNITY; IMMUNOLOGY; LEISHMANIA; METABOLISM; MICROBIOLOGY; MYCOBACTERIUM; PHYSIOLOGY;

IMMUNITY; INFECTION; LEISHMANIA; MYCOBACTERIUM; TRANSITION METAL;

CYTOSOL; HOMEOSTASIS; HOST-PATHOGEN INTERACTIONS; IRON; LEISHMANIA; MYCOBACTERIUM;

EID: 84897926567     PISSN: None     EISSN: 22352988     Source Type: Journal    
DOI: 10.3389/fcimb.2013.00096     Document Type: Review

References (150)

1. Ait-Oudhia, K., Gazanion, E., Vergnes, B., Oury, B., and Sereno, D. (2011). Leishmania antimony resistance: what we know what we can learn from the field. Parasitol. Res. 109, 1225-1232. doi: 10.1007/s00436-011-2555-5.
2. Altet, L., Francino, O., Solano-Gallego, L., Renier, C., and Sanchez, A. (2002). Mapping and sequencing of the canine NRAMP1 gene and identification of mutations in leishmaniasis-susceptible dogs. Infect. Immun. 70, 2763-2771. doi: 10.1128/IAI.70.6.2763-2771.2002.
3. Andreini, C., Bertini, I., Cavallaro, G., Holliday, G. L., and Thornton, J. M. (2008). Metal ions in biological catalysis: from enzyme databases to general principles. J. Biol. Inorg. Chem. 13, 1205-1218. doi: 10.1007/s00775-008-0404-5.
4. Andrews, N. C., and Schmidt, P. J. (2007). Iron homeostasis. Annu. Rev. Physiol. 69, 69-85. doi: 10.1146/annurev.physiol.69.031905.164337.
5. Appelberg, R. (2006a). Macrophage nutriprive antimicrobial mechanisms. J. Leukoc. Biol. 79, 1117-1128. doi: 10.1189/jlb.0206079.
6. Appelberg, R. (2006b). Pathogenesis of Mycobacterium avium infection: typical responses to an atypical mycobacterium? Immunol. Res. 35, 179-190. doi: 10.1385/IR:35:3:179.
7. Appelberg, R., and Sarmento, A. M. (1990). The role of macrophage activation and of Bcg-encoded macrophage function(s) in the control of Mycobacterium avium infection in mice. Clin. Exp. Immunol. 80, 324-331. doi: 10.1111/j.1365-2249.1990.tb03288.x.
8. Artis, D., Speirs, K., Joyce, K., Goldschmidt, M., Caamano, J., Hunter, C. A., et al. (2003). NF-kappa B1 is required for optimal CD4+ Th1 cell development and resistance to Leishmania major. J. Immunol. 170, 1995-2003.
9. Bisti, S., Konidou, G., Boelaert, J., Lebastard, M., and Soteriadou, K. (2006). The prevention of the growth of Leishmania major progeny in BALB/c iron-loaded mice: a process coupled to increased oxidative burst, the amplitude and duration of which depend on initial parasite developmental stage and dose. Microbes Infect. 8, 1464-1472. doi: 10.1016/j.micinf.2006.01.014.
10. Bisti, S., Konidou, G., Papageorgiou, F., Milon, G., Boelaert, J. R., and Soteriadou, K. (2000). The outcome of Leishmania major experimental infection in BALB/c mice can be modulated by exogenously delivered iron. Eur. J. Immunol. 30, 3732-3740. doi: 10.1002/1521-4141(200012)30:12<3732::AID-IMMU3732>3.0.CO;2-D.
11. Bisti, S., and Soteriadou, K. (2006). Is the reactive oxygen species-dependent-NF-kappaB activation observed in iron-loaded BALB/c mice a key process preventing growth of Leishmania major progeny and tissue-damage? Microbes Infect. 8, 1473-1482. doi: 10.1016/j.micinf.2006.01.004.
12. Blackwell, J. M., Fakiola, M., Ibrahim, M. E., Jamieson, S. E., Jeronimo, S. B., Miller, E. N., et al. (2009). Genetics and visceral leishmaniasis: of mice and man. Parasite Immunol. 31, 254-266. doi: 10.1111/j.1365-3024.2009.01102.x.
13. Bonizzi, G., and Karin, M. (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280-288. doi: 10.1016/j.it.2004.03.008.
14. Borges, V. M., Vannier-Santos, M. A., and De Souza, W. (1998). Subverted transferrin trafficking in Leishmania-infected macrophages. Parasitol. Res. 84, 811-822. doi: 10.1007/s004360050493.
15. Botella, H., Peyron, P., Levillain, F., Poincloux, R., Poquet, Y., Brandli, I., et al. (2011). Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe 10, 248-259. doi: 10.1016/j.chom.2011.08.006.
16. Bucheton, B., Abel, L., Kheir, M. M., Mirgani, A., El-Safi, S. H., Chevillard, C., et al. (2003). Genetic control of visceral leishmaniasis in a Sudanese population: candidate gene testing indicates a linkage to the NRAMP1 region. Genes Immun. 4, 104-109. doi: 10.1038/sj.gene.6363927.
17. Carvalho, S., Cruz, T., Santarem, N., Castro, H., Costa, V., and Tomas, A. M. (2009). Heme as a source of iron to Leishmania infantum amastigotes. Acta Trop. 109, 131-135. doi: 10.1016/j.actatropica.2008.10.007.
18. Castellucci, L., Jamieson, S. E., Miller, E. N., Menezes, E., Oliveira, J., Magalhaes, A., et al. (2010). CXCR1 and SLC11A1 polymorphisms affect susceptibility to cutaneous leishmaniasis in Brazil: a case-control and family-based study. BMC Med. Genet. 11:10. doi: 10.1186/1471-2350-11-10.
19. Cellier, M. F., Courville, P., and Campion, C. (2007). Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect. 9, 1662-1670. doi: 10.1016/j.micinf.2007.09.006.
20. Clemens, D. L., and Horwitz, M. A. (1996). The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin. J. Exp. Med. 184, 1349-1355. doi: 10.1084/jem.184.4.1349.
21. Cooper, A. M. (2009). Cell-mediated immune responses in tuberculosis. Annu. Rev. Immunol. 27, 393-422. doi: 10.1146/annurev.immunol.021908.132703.
22. Correnti, C., and Strong, R. K. (2012). Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool. J. Biol. Chem. 287, 13524-13531. doi: 10.1074/jbc.R111.311829.
23. Crichton, R. R., and Pierre, J. L. (2001). Old iron, young copper: from Mars to Venus. Biometals 14, 99-112. doi: 10.1023/A:1016710810701.
24. Das, N. K., Biswas, S., Solanki, S., and Mukhopadhyay, C. K. (2009). Leishmania donovani depletes labile iron pool to exploit iron uptake capacity of macrophage for its intracellular growth. Cell. Microbiol. 11, 83-94. doi: 10.1111/j.1462-5822.2008.01241.x.
25. Deschemin, J. C., and Vaulont, S. (2013). Role of hepcidin in the setting of hypoferremia during acute inflammation. PLoS ONE 8:e61050. doi: 10.1371/journal.pone.0061050.
26. De Sousa, M., Reimao, R., Lacerda, R., Hugo, P., Kaufmann, S. H., and Porto, G. (1994). Iron overload in beta 2-microglobulin-deficient mice. Immunol. Lett. 39, 105-111. doi: 10.1016/0165-2478(94)90094-9.
27. Devireddy, L. R., Gazin, C., Zhu, X., and Green, M. R. (2005). A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123, 1293-1305. doi: 10.1016/j.cell.2005.10.027.
28. De Voss, J. J., Rutter, K., Schroeder, B. G., Su, H., Zhu, Y., and Barry, C. E. 3rd (2000). The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl. Acad. Sci. U.S.A. 97, 1252-1257. doi: 10.1073/pnas.97.3.1252.
29. Fernandes, S. S., Nunes, A., Gomes, A. R., De Castro, B., Hider, R. C., Rangel, M., et al. (2010). Identification of a new hexadentate iron chelator capable of restricting the intramacrophagic growth of Mycobacterium avium. Microbes Infect. 12, 287-294. doi: 10.1016/j.micinf.2010.01.003.
30. Ferreras, J. A., Gupta, A., Amin, N. D., Basu, A., Sinha, B. N., Worgall, S., et al. (2011). Chemical scaffolds with structural similarities to siderophores of nonribosomal peptide-polyketide origin as novel antimicrobials against Mycobacterium tuberculosis and Yersinia pestis. Bioorg. Med. Chem. Lett. 21, 6533-6537. doi: 10.1016/j.bmcl.2011.08.052.
31. Ferreras, J. A., Ryu, J. S., Di Lello, F., Tan, D. S., and Quadri, L. E. (2005). Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat. Chem. Biol. 1, 29-32. doi: 10.1038/nchembio706.
32. Flannery, A. R., Huynh, C., Mittra, B., Mortara, R. A., and Andrews, N. W. (2011). LFR1 ferric iron reductase of Leishmania amazonensis is essential for the generation of infective parasite forms. J. Biol. Chem. 286, 23266-23279. doi: 10.1074/jbc.M111.229674.
33. Flynn, J. L., Goldstein, M. M., Triebold, K. J., Koller, B., and Bloom, B. R. (1992). Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. U.S.A. 89, 12013-12017. doi: 10.1073/pnas.89.24.12013.
34. Forbes, J. R., and Gros, P. (2003). Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102, 1884-1892. doi: 10.1182/blood-2003-02-0425.
35. Fortier, A., Min-Oo, G., Forbes, J., Lam-Yuk-Tseung, S., and Gros, P. (2005). Single gene effects in mouse models of host: pathogen interactions. J. Leukoc. Biol. 77, 868-877. doi: 10.1189/jlb.1004616.
36. Galaris, D., and Pantopoulos, K. (2008). Oxidative stress and iron homeostasis: mechanistic and health aspects. Crit. Rev. Clin. Lab. Sci. 45, 1-23. doi: 10.1080/10408360701713104.
37. Gangaidzo, I. T., Moyo, V. M., Mvundura, E., Aggrey, G., Murphree, N. L., Khumalo, H., et al. (2001). Association of pulmonary tuberculosis with increased dietary iron. J. Infect. Dis. 184, 936-939. doi: 10.1086/323203.
38. Ganz, T., and Nemeth, E. (2012a). Hepcidin and iron homeostasis. Biochim. Biophys. Acta 1823, 1434-1443. doi: 10.1016/j.bbamcr.2012.01.014.
39. Ganz, T., and Nemeth, E. (2012b). Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harb. Perspect. Med. 2, a011668. doi: 10.1101/cshperspect.a011668.
40. Garg, R., Singh, N., and Dube, A. (2004). Intake of nutrient supplements affects multiplication of Leishmania donovani in hamsters. Parasitology 129, 685-691. doi: 10.1017/S0031182004006055.
41. Gobin, J., and Horwitz, M. A. (1996). Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall. J. Exp. Med. 183, 1527-1532. doi: 10.1084/jem.183.4.1527.
42. Goetz, D. H., Holmes, M. A., Borregaard, N., Bluhm, M. E., Raymond, K. N., and Strong, R. K. (2002). The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10, 1033-1043. doi: 10.1016/S1097-2765(02)00708-6.
43. Gomes, M. S., and Appelberg, R. (1998). Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium. Immunology 95, 165-168. doi: 10.1046/j.1365-2567.1998.00630.x.
44. Gomes, M. S., and Appelberg, R. (2002). NRAMP1-or cytokine-induced bacteriostasis of Mycobacterium avium by mouse macrophages is independent of the respiratory burst. Microbiology 148, 3155-3160.
45. Gomes, M. S., Boelaert, J. R., and Appelberg, R. (2001). Role of iron in experimental Mycobacterium avium infection. J. Clin. Virol. 20, 117-122. doi: 10.1016/S1386-6532(00)00135-9.
46. Gomes, M. S., Dom, G., Pedrosa, J., Boelaert, J. R., and Appelberg, R. (1999a). Effects of iron deprivation on Mycobacterium avium growth. Tuber. Lung Dis. 79, 321-328. doi: 10.1054/tuld.1999.0216.
47. Gomes, M. S., Florido, M., Pais, T. F., and Appelberg, R. (1999b). Improved clearance of Mycobacterium avium upon disruption of the inducible nitric oxide synthase gene. J. Immunol. 162, 6734-6739.
48. Gomes-Pereira, S., Rodrigues, P. N., Appelberg, R., and Gomes, M. S. (2008). Increased susceptibility to Mycobacterium avium in hemochromatosis protein HFE-deficient mice. Infect. Immun. 76, 4713-4719. doi: 10.1128/IAI.00612-08.
49. Gordeuk, V. R., McLaren, C. E., Macphail, A. P., Deichsel, G., and Bothwell, T. H. (1996). Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited. Blood 87, 3470-3476.
50. Goto, Y., Buschman, E., and Skamene, E. (1989). Regulation of host resistance to Mycobacterium intracellulare in vivo and in vitro by the Bcg gene. Immunogenetics 30, 218-221. doi: 10.1007/BF02421210.
51. Gros, P., Skamene, E., and Forget, A. (1981). Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice. J. Immunol. 127, 2417-2421.
52. Halaas, O., Steigedal, M., Haug, M., Awuh, J. A., Ryan, L., Brech, A., et al. (2010). Intracellular Mycobacterium avium intersect transferrin in the Rab11(+) recycling endocytic pathway and avoid lipocalin 2 trafficking to the lysosomal pathway. J. Infect. Dis. 201, 783-792. doi: 10.1086/650493.
53. Harrison, P. M., and Arosio, P. (1996). The ferritins: molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta 1275, 161-203. doi: 10.1016/0005-2728(96)00022-9.
54. Hider, R. C., and Kong, X. (2010). Chemistry and biology of siderophores. Nat. Prod. Rep. 27, 637-657. doi: 10.1039/b906679a.
55. Hodgkinson, V., and Petris, M. J. (2012). Copper homeostasis at the host-pathogen interface. J. Biol. Chem. 287, 13549-13555. doi: 10.1074/jbc.R111.316406.
56. Holmes, M. A., Paulsene, W., Jide, X., Ratledge, C., and Strong, R. K. (2005). Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure 13, 29-41. doi: 10.1016/j.str.2004.10.009.
57. Hood, M. I., and Skaar, E. P. (2012). Nutritional immunity: transition metals at the pathogen-host interface. Nat. Rev. Microbiol. 10, 525-537. doi: 10.1038/nrmicro2836.
58. Huynh, C., Sacks, D. L., and Andrews, N. W. (2006). A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes. J. Exp. Med. 203, 2363-2375. doi: 10.1084/jem.20060559.
59. Huynh, C., Yuan, X., Miguel, D. C., Renberg, R. L., Protchenko, O., Philpott, C. C., et al. (2012). Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog. 8:e1002795. doi: 10.1371/journal.ppat.1002795.
60. Jacques, I., Andrews, N. W., and Huynh, C. (2010). Functional characterization of LIT1, the Leishmania amazonensis ferrous iron transporter. Mol. Biochem. Parasitol. 170, 28-36. doi: 10.1016/j.molbiopara.2009.12.003.
61. Johnson, E. E., Sandgren, A., Cherayil, B. J., Murray, M., and Wessling-Resnick, M. (2010). Role of ferroportin in macrophage-mediated immunity. Infect. Immun. 78, 5099-5106. doi: 10.1128/IAI.00498-10.
62. Jones, C. M., and Niederweis, M. (2011). Mycobacterium tuberculosis can utilize heme as an iron source. J. Bacteriol. 193, 1767-1770. doi: 10.1128/JB.01312-10.
63. Kaplan, J., and Ward, D. M. (2013). The essential nature of iron usage and regulation. Curr. Biol. 23, R642-R646. doi: 10.1016/j.cub.2013.05.033.
64. Kaye, P., and Scott, P. (2011). Leishmaniasis: complexity at the host-pathogen interface. Nat. Rev. Microbiol. 9, 604-615. doi: 10.1038/nrmicro2608.
65. Kehl-Fie, T. E., and Skaar, E. P. (2010). Nutritional immunity beyond iron: a role for manganese and zinc. Curr. Opin. Chem. Biol. 14, 218-224. doi: 10.1016/j.cbpa.2009.11.008.
66. Kelley, V. A., and Schorey, J. S. (2003). Mycobacterium's arrest of phagosome maturation in macrophages requires Rab5 activity and accessibility to iron. Mol. Biol. Cell 14, 3366-3377. doi: 10.1091/mbc.E02-12-0780.
67. Knutson, M. D., Oukka, M., Koss, L. M., Aydemir, F., and Wessling-Resnick, M. (2005). Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc. Natl. Acad. Sci. U.S.A. 102, 1324-1328. doi: 10.1073/pnas.0409409102.
68. Kuhn, D. E., Baker, B. D., Lafuse, W. P., and Zwilling, B. S. (1999). Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169. J. Leukoc. Biol. 66, 113-119.
69. Kuhn, D. E., Lafuse, W. P., and Zwilling, B. S. (2001). Iron transport into mycobacterium avium-containing phagosomes from an Nramp1(Gly169)-transfected RAW264.7 macrophage cell line. J. Leukoc. Biol. 69, 43-49.
70. Laftah, A. H., Sharma, N., Brookes, M. J., McKie, A. T., Simpson, R. J., Iqbal, T. H., et al. (2006). Tumour necrosis factor alpha causes hypoferraemia and reduced intestinal iron absorption in mice. Biochem. J. 397, 61-67. doi: 10.1042/BJ20060215.
71. Larsen, R., Gozzelino, R., Jeney, V., Tokaji, L., Bozza, F. A., Japiassu, A. M., et al. (2010). A central role for free heme in the pathogenesis of severe sepsis. Sci. Transl. Med. 2, 51ra71. doi: 10.1126/scitranslmed.3001118.
72. Layoun, A., Huang, H., Calve, A., and Santos, M. M. (2012). Toll-like receptor signal adaptor protein MyD88 is required for sustained endotoxin-induced acute hypoferremic response in mice. Am. J. Pathol. 180, 2340-2350. doi: 10.1016/j.ajpath.2012.01.046.
73. Lee, S. W., Kang, Y. A., Yoon, Y. S., Um, S. W., Lee, S. M., Yoo, C. G., et al. (2006). The prevalence and evolution of anemia associated with tuberculosis. J. Korean Med. Sci. 21, 1028-1032. doi: 10.3346/jkms.2006.21.6.1028.
74. Leonard, S. S., Harris, G. K., and Shi, X. (2004). Metal-induced oxidative stress and signal transduction. Free Radic. Biol. Med. 37, 1921-1942. doi: 10.1016/j.freeradbiomed.2004.09.010.
75. Lounis, N., Maslo, C., Boelaert, J. R., Bonnafous, P., Truffot-Pernot, C., Baohong, J., et al. (1999). Impact of iron loading and iron chelation on murine tuberculosis. Clin. Microbiol. Infect. 5, 687-692. doi: 10.1111/j.1469-0691.1999.tb00514.x.
76. Lounis, N., Maslo, C., Truffot-Pernot, C., Grosset, J., and Boelaert, R. J. (2003). Impact of iron loading on the activity of isoniazid or ethambutol in the treatment of murine tuberculosis. Int. J. Tuberc. Lung Dis. 7, 575-579.
77. Lounis, N., Truffot-Pernot, C., Grosset, J., Gordeuk, V. R., and Boelaert, J. R. (2001). Iron and Mycobacterium tuberculosis infection. J. Clin. Virol. 20, 123-126. doi: 10.1016/S1386-6532(00)00136-0.
78. Lun, S., Guo, H., Adamson, J., Cisar, J. S., Davis, T. D., Chavadi, S. S., et al. (2013). Pharmacokinetic and in vivo efficacy studies of the Mycobactin biosynthesis inhibitor Salicyl-AMS in Mice. Antimicrob. Agents Chemother. 57, 5138-5140. doi: 10.1128/AAC.00918-13.
79. Maciel, B. L., Lacerda, H. G., Queiroz, J. W., Galvao, J., Pontes, N. N., Dimenstein, R., et al. (2008). Association of nutritional status with the response to infection with Leishmania chagasi. Am. J. Trop. Med. Hyg. 79, 591-598.
80. Malafaia, G., Marcon Lde, N., Pereira Lde, F., Pedrosa, M. L., and Rezende, S. A. (2011). Leishmania chagasi: effect of the iron deficiency on the infection in BALB/c mice. Exp. Parasitol. 127, 719-723. doi: 10.1016/j.exppara.2010.11.010.
81. Marchal, G., and Milon, G. (1981). Decreased erythropoiesis: the origin of the BCG induced anaemia in mice. Br. J. Haematol. 48, 551-560. doi: 10.1111/j.1365-2141.1981.tb02752.x.
82. Mauel, J., Ransijn, A., and Buchmuller-Rouiller, Y. (1991). Killing of Leishmania parasites in activated murine macrophages is based on an L-arginine-dependent process that produces nitrogen derivatives. J. Leukoc. Biol. 49, 73-82.
83. McCall, L. I., Zhang, W. W., and Matlashewski, G. (2013). Determinants for the development of visceral leishmaniasis disease. PLoS Pathog. 9:e1003053. doi: 10.1371/journal.ppat.1003053.
84. McDermid, J. M., Hennig, B. J., Van Der Sande, M., Hill, A. V., Whittle, H. C., Jaye, A., et al. (2013). Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study. BMC Infect. Dis. 13:48. doi: 10.1186/1471-2334-13-48.
85. Medina, E., and North, R. J. (1996). Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice to infection with virulent Mycobacterium tuberculosis. J. Exp. Med. 183, 1045-1051. doi: 10.1084/jem.183.3.1045.
86. Meyer, D. (2006). Iron chelation as therapy for HIV and Mycobacterium tuberculosis co-infection under conditions of iron overload. Curr. Pharm. Des. 12, 1943-1947. doi: 10.2174/138161206777442164.
87. Mittra, B., Cortez, M., Haydock, A., Ramasamy, G., Myler, P. J., and Andrews, N. W. (2013). Iron uptake controls the generation of Leishmania infective forms through regulation of ROS levels. J. Exp. Med. 210, 401-416. doi: 10.1084/jem.20121368.
88. Moniz, T., Nunes, A., Silva, A. M., Queiros, C., Ivanova, G., Gomes, M. S., et al. (2013). Rhodamine labeling of 3-hydroxy-4-pyridinone iron chelators is an important contribution to target Mycobacterium avium infection. J. Inorg. Biochem. 121, 156-166. doi: 10.1016/j.jinorgbio.2013.01.002.
89. Mulero, V., Searle, S., Blackwell, J. M., and Brock, J. H. (2002). Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake. Biochem. J. 363, 89-94. doi: 10.1042/0264-6021:3630089.
90. Murray, H. W., Granger, A. M., and Teitelbaum, R. F. (1991). Gamma interferon-activated human macrophages and Toxoplasma gondii, Chlamydia psittaci, and Leishmania donovani: antimicrobial role of limiting intracellular iron. Infect. Immun. 59, 4684-4686.
91. Nairz, M., Schleicher, U., Schroll, A., Sonnweber, T., Theurl, I., Ludwiczek, S., et al. (2013). Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. J. Exp. Med. 210, 855-873. doi: 10.1084/jem.20121946.
92. Nairz, M., Theurl, I., Ludwiczek, S., Theurl, M., Mair, S. M., Fritsche, G., et al. (2007). The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell. Microbiol. 9, 2126-2140. doi: 10.1111/j.1462-5822.2007.00942.x.
93. Nambu, S., Matsui, T., Goulding, C. W., Takahashi, S., and Ikeda-Saito, M. (2013). A new way to degrade heme: the Mycobacterium tuberculosis enzyme MhuD catalyzes heme degradation without generating CO. J. Biol. Chem. 288, 10101-10109. doi: 10.1074/jbc.M112.448399.
94. Nevo, Y., and Nelson, N. (2006). The NRAMP family of metal-ion transporters. Biochim. Biophys. Acta 1763, 609-620. doi: 10.1016/j.bbamcr.2006.05.007.
95. Nguyen, K. T., Wu, J. C., Boylan, J. A., Gherardini, F. C., and Pei, D. (2007). Zinc is the metal cofactor of Borrelia burgdorferi peptide deformylase. Arch. Biochem. Biophys. 468, 217-225. doi: 10.1016/j.abb.2007.09.023.
96. North, R. J., Lacourse, R., Ryan, L., and Gros, P. (1999). Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice. Infect. Immun. 67, 5811-5814.
97. Nunes, A., Podinovskaia, M., Leite, A., Gameiro, P., Zhou, T., Ma, Y., et al. (2010). Fluorescent 3-hydroxy-4-pyridinone hexadentate iron chelators: intracellular distribution and the relevance to antimycobacterial properties. J. Biol. Inorg. Chem. 15, 861-877. doi: 10.1007/s00775-010-0650-1.
98. Olakanmi, O., Schlesinger, L. S., Ahmed, A., and Britigan, B. E. (2002). Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. J. Biol. Chem. 277, 49727-49734. doi: 10.1074/jbc.M209768200.
99. Olakanmi, O., Schlesinger, L. S., Ahmed, A., and Britigan, B. E. (2004). The nature of extracellular iron influences iron acquisition by Mycobacterium tuberculosis residing within human macrophages. Infect. Immun. 72, 2022-2028. doi: 10.1128/IAI.72.4.2022-2028.2004.
100. Olakanmi, O., Schlesinger, L. S., and Britigan, B. E. (2007). Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J. Leukoc. Biol. 81, 195-204. doi: 10.1189/jlb.0606405.
101. Posey, J. E., and Gherardini, F. C. (2000). Lack of a role for iron in the Lyme disease pathogen. Science 288, 1651-1653. doi: 10.1126/science.288.5471.1651.
102. Quadri, L. E., Sello, J., Keating, T. A., Weinreb, P. H., and Walsh, C. T. (1998). Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem. Biol. 5, 631-645. doi: 10.1016/S1074-5521(98)90291-5.
103. Ratledge, C. (2004). Iron, mycobacteria and tuberculosis. Tuberculosis 84, 110-130. doi: 10.1016/j.tube.2003.08.012.
104. Ready, P. D. (2010). Leishmaniasis emergence in Europe. Euro Surveill. 15, 19505.
105. Recalcati, S., Locati, M., and Cairo, G. (2012). Systemic and cellular consequences of macrophage control of iron metabolism. Semin. Immunol. 24, 393. doi: 10.1016/j.smim.2013.01.001.
106. Reddy, P. V., Puri, R. V., Chauhan, P., Kar, R., Rohilla, A., Khera, A., and Tyagi, A. K. (2013). Disruption of Mycobactin biosynthesis leads to attenuation of Mycobacterium tuberculosis for growth and virulence. J. Infect. Dis. 208, 1255-1265. doi: 10.1093/infdis/jit250.
107. Rocha, M. N., Nogueira, P. M., Demicheli, C., De Oliveira, L. G., Da Silva, M. M., Frezard, F., et al. (2013). Cytotoxicity and in vitro antileishmanial activity of antimony (V), Bismuth (V), and Tin (IV) complexes of lapachol. Bioinorg. Chem. Appl. 2013:961783. doi: 10.1155/2013/961783.
108. Rodrigues, P. N., Gomes, S. S., Neves, J. V., Gomes-Pereira, S., Correia-Neves, M., Nunes-Alves, C., et al. (2011). Mycobacteria-induced anaemia revisited: a molecular approach reveals the involvement of NRAMP1 and lipocalin-2, but not of hepcidin. Immunobiology 216, 1127-1134. doi: 10.1016/j.imbio.2011.04.004.
109. Rodriguez, G. M., and Smith, I. (2006). Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J. Bacteriol. 188, 424-430. doi: 10.1128/JB.188.2.424-430.2006.
110. Rolph, M. S., Raupach, B., Kobernick, H. H., Collins, H. L., Perarnau, B., Lemonnier, F. A., et al. (2001). MHC class Ia-restricted T cells partially account for beta2-microglobulin-dependent resistance to Mycobacterium tuberculosis. Eur. J. Immunol. 31, 1944-1949. doi: 10.1002/1521-4141(200106)31:6<1944::AID-IMMU1944>3.0.CO;2-R.
111. Rowland, J. L., and Niederweis, M. (2012). Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload. Tuberculosis 92, 202-210. doi: 10.1016/j.tube.2011.12.006.
112. Roy, C. N. (2010). Anemia of inflammation. Hematology Am. Soc. Hematol. Educ. Program 2010, 276-280. doi: 10.1182/asheducation-2010.1.276.
113. Sahiratmadja, E., Wieringa, F. T., Van Crevel, R., De Visser, A. W., Adnan, I., Alisjahbana, B., et al. (2007). Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3'UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population. Br. J. Nutr. 98, 684-690. doi: 10.1017/S0007114507742691.
114. Saiga, H., Nishimura, J., Kuwata, H., Okuyama, M., Matsumoto, S., Sato, S., et al. (2008). Lipocalin 2-dependent inhibition of mycobacterial growth in alveolar epithelium. J. Immunol. 181, 8521-8527.
115. Sanchez-Robert, E., Altet, L., Utzet-Sadurni, M., Giger, U., Sanchez, A., and Francino, O. (2008). Slc11a1 (formerly Nramp1) and susceptibility to canine visceral leishmaniasis. Vet. Res. 39, 36. doi: 10.1051/vetres:2008013.
116. Schaible, U. E., Collins, H. L., Priem, F., and Kaufmann, S. H. (2002). Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J. Exp. Med. 196, 1507-1513. doi: 10.1084/jem.20020897.
117. Schaible, U. E., and Kaufmann, S. H. (2004). Iron and microbial infection. Nat. Rev. Microbiol. 2, 946-953. doi: 10.1038/nrmicro1046.
118. Schubert, T. E., Bosserhoff, A. K., Peyssonaux, C., Echtenacher, B., Knutson, M., Hofstadter, F., et al. (2012). Hypoferraemia during the early inflammatory response is dependent on tumour necrosis factor activity in a murine model of protracted peritonitis. Mol. Med. Rep. 6, 838-842. doi: 10.3892/mmr.2012.1004.
119. Searle, S., Bright, N. A., Roach, T. I., Atkinson, P. G., Barton, C. H., Meloen, R. H., et al. (1998). Localisation of Nramp1 in macrophages: modulation with activation and infection. J. Cell Sci. 111(Pt 19), 2855-2866.
120. Segal, B. H., Doherty, T. M., Wynn, T. A., Cheever, A. W., Sher, A., and Holland, S. M. (1999). The p47(phox-/-) mouse model of chronic granulomatous disease has normal granuloma formation and cytokine responses to Mycobacterium avium and Schistosoma mansoni eggs. Infect. Immun. 67, 1659-1665.
121. Segovia, M., Navarro, A., and Artero, J. M. (1989). The effect of liposome-entrapped desferrioxamine on Leishmania donovani in vitro. Ann. Trop. Med. Parasitol. 83, 357-360.
122. Silva-Gomes, S., Appelberg, R., Larsen, R., Soares, M. P., and Gomes, M. S. (2013a). Heme catabolism by heme oxygenase-1 confers host resistance to Mycobacterium infection. Infect. Immun. 81, 2536-2545. doi: 10.1128/IAI.00251-13.
123. Silva-Gomes, S., Bouton, C., Silva, T., Santambrogio, P., Rodrigues, P., Appelberg, R., et al. (2013b). Mycobacterium avium infection induces H-Ferritin expression in mouse primary macrophages by activating Toll-like receptor 2. PLoS ONE e82874. doi: 10.1371/journal.pone.0082874.
124. Singh, N., Bajpai, S., Kumar, V., Gour, J. K., and Singh, R. K. (2013). Identification and functional characterization of Leishmania donovani secretory peroxidase: delineating its role in NRAMP1 regulation. PLoS ONE 8:e53442. doi: 10.1371/journal.pone.0053442.
125. Soe-Lin, S., Apte, S. S., Andriopoulos, B. Jr., Andrews, M. C., Schranzhofer, M., Kahawita, T., et al. (2009). Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc. Natl. Acad. Sci. U.S.A. 106, 5960-5965. doi: 10.1073/pnas.0900808106.
126. Soo, S. S., Villarreal-Ramos, B., Anjam Khan, C. M., Hormaeche, C. E., and Blackwell, J. M. (1998). Genetic control of immune response to recombinant antigens carried by an attenuated Salmonella typhimurium vaccine strain: Nramp1 influences T-helper subset responses and protection against leishmanial challenge. Infect. Immun. 66, 1910-1917.
127. Soteriadou, K., Papavassiliou, P., Voyiatzaki, C., and Boelaert, J. (1995). Effect of iron chelation on the in-vitro growth of Leishmania promastigotes. J. Antimicrob. Chemother. 35, 23-29. doi: 10.1093/jac/35.1.23.
128. Sow, F. B., Florence, W. C., Satoskar, A. R., Schlesinger, L. S., Zwilling, B. S., and Lafuse, W. P. (2007). Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J. Leukoc. Biol. 82, 934-945. doi: 10.1189/jlb.0407216.
129. Sutak, R., Lesuisse, E., Tachezy, J., and Richardson, D. R. (2008). Crusade for iron: iron uptake in unicellular eukaryotes and its significance for virulence. Trends Microbiol. 16, 261-268. doi: 10.1016/j.tim.2008.03.005.
130. Taylor, M. C., and Kelly, J. M. (2010). Iron metabolism in trypanosomatids, and its crucial role in infection. Parasitology 137, 899-917. doi: 10.1017/S0031182009991880.
131. Trousseau, A. (1872). True, False Chlorosis. Lectures on Clinical Medicine. Philadelphia, PA: Lindsay and Blakiston.
132. Tullius, M. V., Harmston, C. A., Owens, C. P., Chim, N., Morse, R. P., McMath, L. M., et al. (2011). Discovery and characterization of a unique mycobacterial heme acquisition system. Proc. Natl. Acad. Sci. U.S.A. 108, 5051-5056. doi: 10.1073/pnas.1009516108.
133. Vale-Costa, S., Gomes-Pereira, S., Teixeira, C. M., Rosa, G., Rodrigues, P. N., Tomas, A., et al. (2013). Iron overload favors the elimination of Leishmania infantum from mouse tissues through interaction with reactive oxygen and nitrogen species. PLoS Negl. Trop. Dis. 7:e2061. doi: 10.1371/journal.pntd.0002061.
134. Vale-Costa, S., Vale, N., Matos, J., Tomas, A., Moreira, R., Gomes, P., et al. (2012). Peptidomimetic and organometallic derivatives of primaquine active against Leishmania infantum. Antimicrob. Agents Chemother. 56, 5774-5781. doi: 10.1128/AAC.00873-12.
135. Van Zandt, K. E., Sow, F. B., Florence, W. C., Zwilling, B. S., Satoskar, A. R., Schlesinger, L. S., et al. (2008). The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial-containing phagosome. J. Leukoc. Biol. 84, 689-700. doi: 10.1189/jlb.1107781.
136. Vidal, S. M., Malo, D., Vogan, K., Skamene, E., and Gros, P. (1993). Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469-485. doi: 10.1016/0092-8674(93)90135-D.
137. Vidal, S., Tremblay, M. L., Govoni, G., Gauthier, S., Sebastiani, G., Malo, D., et al. (1995). The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J. Exp. Med. 182, 655-666. doi: 10.1084/jem.182.3.655.
138. Wagner, D., Maser, J., Lai, B., Cai, Z., Barry, C. E. 3rd., Honer Zu Bentrup, K., et al. (2005). Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell's endosomal system. J. Immunol. 174, 1491-1500.
139. Weinberg, E. D. (2009). Iron availability and infection. Biochim. Biophys. Acta 1790, 600-605. doi: 10.1016/j.bbagen.2008.07.002.
140. Weiss, G. (2009). Iron metabolism in the anemia of chronic disease. Biochim. Biophys. Acta 1790, 682-693. doi: 10.1016/j.bbagen.2008.08.006.
141. Wells, R. M., Jones, C. M., Xi, Z., Speer, A., Danilchanka, O., Doornbos, K. S., et al. (2013). Discovery of a siderophore export system essential for virulence of Mycobacterium tuberculosis. PLoS Pathog. 9:e1003120. doi: 10.1371/journal.ppat.1003120.
142. Wessling-Resnick, M. (2010). Iron homeostasis and the inflammatory response. Annu. Rev. Nutr. 30, 105-122. doi: 10.1146/annurev.nutr.012809.104804.
143. White, C., Lee, J., Kambe, T., Fritsche, K., and Petris, M. J. (2009). A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J. Biol. Chem. 284, 33949-33956. doi: 10.1074/jbc.M109.070201.
144. White, J. K., Mastroeni, P., Popoff, J. F., Evans, C. A., and Blackwell, J. M. (2005). Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity. J. Leukoc. Biol. 77, 311-320. doi: 10.1189/jlb.0904546.
145. White, J. K., Stewart, A., Popoff, J. F., Wilson, S., and Blackwell, J. M. (2004). Incomplete glycosylation and defective intracellular targeting of mutant solute carrier family 11 member 1 (Slc11a1). Biochem. J. 382, 811-819. doi: 10.1042/BJ20040808.
146. Wolschendorf, F., Ackart, D., Shrestha, T. B., Hascall-Dove, L., Nolan, S., Lamichhane, G., et al. (2011). Copper resistance is essential for virulence of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U.S.A. 108, 1621-1626. doi: 10.1073/pnas.1009261108.
147. Xiong, S., She, H., Takeuchi, H., Han, B., Engelhardt, J. F., Barton, C. H., et al. (2003). Signaling role of intracellular iron in NF-kappaB activation. J. Biol. Chem. 278, 17646-17654. doi: 10.1074/jbc.M210905200.
148. Yang, F., Liu, X. B., Quinones, M., Melby, P. C., Ghio, A., and Haile, D. J. (2002). Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J. Biol. Chem. 277, 39786-39791. doi: 10.1074/jbc.M201485200.
149. Zhou, X. Y., Tomatsu, S., Fleming, R. E., Parkkila, S., Waheed, A., Jiang, J., et al. (1998). HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc. Natl. Acad. Sci. U.S.A. 95, 2492-2497. doi: 10.1073/pnas.95.5.2492.
150. Zwilling, B. S., Kuhn, D. E., Wikoff, L., Brown, D., and Lafuse, W. (1999). Role of iron in Nramp1-mediated inhibition of mycobacterial growth. Infect. Immun. 67, 1386-1392.