Hostname: page-component-8448b6f56d-c4f8m Total loading time: 0 Render date: 2024-04-19T05:18:54.783Z Has data issue: false hasContentIssue false
  • English
  • Français

Iron acquisition in Leishmania and its crucial role in infection

Published online by Cambridge University Press:  25 May 2016

QINWANG NIU ,
SHIHONG LI ,
DALI CHEN ,
QIWEI CHEN  and
JIANPING CHEN
QINWANG NIU
Affiliation:
Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China Sichuan Engineering Technical College, Deyang, Sichuan 618000, China
SHIHONG LI
Affiliation:
The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, China
DALI CHEN
Affiliation:
Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
QIWEI CHEN
Affiliation:
Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
JIANPING CHEN*
Affiliation:
Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
*
*Corresponding author: Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, NO.17, Third part Ren Min Road, Chengdu, Sichuan, China. E-mail: jpchen1965@163.com
Get access Rights & Permissions [Opens in a new window]

Summary

Iron is an essential cofactor for many basic metabolic pathways in pathogenic microbes and their hosts. It is also dangerous as it can catalyse the production of reactive free radicals. This dual character makes the host can either limit iron availability to invading microbes or exploit iron to induce toxicity to pathogens. Successful pathogens, including Leishmania species, must possess mechanisms to circumvent host's iron limitation and iron-induced toxicity in order to survive. In this review, we discuss the regulation of iron metabolism in the setting of infection and delineate the iron acquisition strategies used by Leishmania parasites and their subversions to host iron metabolism to overcome host's iron-related defences.

Keywords

ironLeishmaniairon acquisitionsubversion
Type
Review Article
Information
Parasitology , Volume 143 , Issue 11 , September 2016 , pp. 1347 - 1357
Check for updates
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Abboud, S. and Haile, D. J. (2000). A novel mammalian iron-regulated protein involved in intracellular iron metabolism. Journal of Biological Chemistry 275, 19906–19912.Google Scholar
Adamec, J., Rusnak, F., Owen, W. G., Naylor, S., Benson, L. M., Gacy, A. M. and Isaya, G. (2000). Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. American Journal of Human Genetics 67, 549–562.Google Scholar
Afeltra, A., Caccavo, D., Ferri, G. M., Addessi, M. A., De Rosa, F. G., Amoroso, A. and Bonomo, L. (1997). Expression of lactoferrin on human granulocytes: analysis with polyclonal and monoclonal antibodies. Clinical and Experimental Immunology 109, 279–285.Google Scholar
Agarwal, S., Rastogi, R., Gupta, D., Patel, N., Raje, M. and Mukhopadhyay, A. (2013). Clathrin-mediated hemoglobin endocytosis is essential for survival of Leishmania . Biochimica et Biophysica Acta 1833, 1065–1077.Google Scholar
Alvar, J., Velez, I. D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J., den Boer, M. and Team, W. H. O. L. C. (2012). Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7, e35671.CrossRefGoogle ScholarPubMed
Alves, J. M., Voegtly, L., Matveyev, A. V., Lara, A. M., da Silva, F. M., Serrano, M. G., Buck, G. A., Teixeira, M. M. and Camargo, E. P. (2011). Identification and phylogenetic analysis of heme synthesis genes in trypanosomatids and their bacterial endosymbionts. PLoS ONE 6, e23518.CrossRefGoogle ScholarPubMed
Andrade, J. M. and Murta, S. M. (2014). Functional analysis of cytosolic tryparedoxin peroxidase in antimony-resistant and -susceptible Leishmania braziliensis and Leishmania infantum lines. Parasites & Vectors 7, 406.CrossRefGoogle ScholarPubMed
Andrews, N. C. and Schmidt, P. J. (2007). Iron homeostasis. Annual Review of Physiology 69, 69–85.Google Scholar
Arango Duque, G., Fukuda, M., Turco, S. J., Stager, S. and Descoteaux, A. (2014). Leishmania promastigotes induce cytokine secretion in macrophages through the degradation of synaptotagmin XI. Journal of Immunology 193, 2363–2372.CrossRefGoogle ScholarPubMed
Arantes, J. M., Pedrosa, M. L., Martins, H. R., Veloso, V. M., de Lana, M., Bahia, M. T., Tafuri, W. L. and Carneiro, C. M. (2007). Trypanosoma cruzi: treatment with the iron chelator desferrioxamine reduces parasitemia and mortality in experimentally infected mice. Experimental Parasitology 117, 43–50.CrossRefGoogle ScholarPubMed
Armitage, A. E., Eddowes, L. A., Gileadi, U., Cole, S., Spottiswoode, N., Selvakumar, T. A., Ho, L. P., Townsend, A. R. and Drakesmith, H. (2011). Hepcidin regulation by innate immune and infectious stimuli. Blood 118, 4129–4139.CrossRefGoogle ScholarPubMed
Baker, H. M. and Baker, E. N. (2012). A structural perspective on lactoferrin function. Biochemistry and Cell Biology 90, 320–328.CrossRefGoogle ScholarPubMed
Ben-Othman, R., Flannery, A. R., Miguel, D. C., Ward, D. M., Kaplan, J. and Andrews, N. W. (2014). Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLoS Pathogens 10, e1003901.CrossRefGoogle ScholarPubMed
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 and Infection 8, 1473–1482.Google Scholar
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. European Journal of Immunology 30, 3732–3740.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
Blackwell, J. M., Fakiola, M., Ibrahim, M. E., Jamieson, S. E., Jeronimo, S. B., Miller, E. N., Mishra, A., Mohamed, H. S., Peacock, C. S., Raju, M., Sundar, S. and Wilson, M. E. (2009). Genetics and visceral leishmaniasis: of mice and man. Parasite Immunology 31, 254–266.Google Scholar
Bonaccorsi-Riani, E., Danger, R., Lozano, J. J., Martinez-Picola, M., Kodela, E., Mas-Malavila, R., Bruguera, M., Collins, H. L., Hider, R. C., Martinez-Llordella, M. and Sanchez-Fueyo, A. (2015). Iron deficiency impairs intra-hepatic lymphocyte mediated immune response. PLoS ONE 10, e0136106.Google Scholar
Borges, V. M., Vannier-Santos, M. A. and de Souza, W. (1998). Subverted transferrin trafficking in Leishmania-infected macrophages. Parasitology Research 84, 811–822.Google Scholar
Bottger, L. H., Miller, E. P., Andresen, C., Matzanke, B. F., Kupper, F. C. and Carrano, C. J. (2012). Atypical iron storage in marine brown algae: a multidisciplinary study of iron transport and storage in Ectocarpus siliculosus . Journal of Experimental Botany 63, 5763–5772.Google Scholar
Bucheton, B., Abel, L., Kheir, M. M., Mirgani, A., El-Safi, S. H., Chevillard, C. and Dessein, A. (2003). Genetic control of visceral leishmaniasis in a Sudanese population: candidate gene testing indicates a linkage to the NRAMP1 region. Genes and Immunity 4, 104–109.CrossRefGoogle Scholar
Bullen, J. J., Rogers, H. J., Spalding, P. B. and Ward, C. G. (2005). Iron and infection: the heart of the matter. FEMS Immunology and Medical Microbiology 43, 325–330.CrossRefGoogle ScholarPubMed
Byrd, T. F. and Horwitz, M. A. (1989). Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. Journal of Clinical Investigation 83, 1457–1465.Google Scholar
Campos-Salinas, J., Cabello-Donayre, M., Garcia-Hernandez, R., Perez-Victoria, I., Castanys, S., Gamarro, F. and Perez-Victoria, J. M. (2011). A new ATP-binding cassette protein is involved in intracellular haem trafficking in Leishmania . Molecular Microbiology 79, 1430–1444.Google Scholar
Cassat, J. E. and Skaar, E. P. (2013). Iron in infection and immunity. Cell Host & Microbe 13, 509–519.CrossRefGoogle ScholarPubMed
Castellucci, L., Jamieson, S. E., Miller, E. N., Menezes, E., Oliveira, J., Magalhaes, A., Guimaraes, L. H., Lessa, M., de Jesus, A. R., Carvalho, E. M. and Blackwell, J. M. (2010). CXCR1 and SLC11A1 polymorphisms affect susceptibility to cutaneous leishmaniasis in Brazil: a case-control and family-based study. BMC Medical Genetics 11, 10.Google Scholar
Caza, M. and Kronstad, J. W. (2013). Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Frontiers in Cellular and Infection Microbiology 3, 80.Google Scholar
Collins, H. L., Kaufmann, S. H. and Schaible, U. E. (2002). Iron chelation via deferoxamine exacerbates experimental salmonellosis via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase-dependent respiratory burst. Journal of Immunology 168, 3458–3463.Google Scholar
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. Cellular Microbiology 11, 83–94.CrossRefGoogle ScholarPubMed
Delaby, C., Rondeau, C., Pouzet, C., Willemetz, A., Pilard, N., Desjardins, M. and Canonne-Hergaux, F. (2012). Subcellular localization of iron and heme metabolism related proteins at early stages of erythrophagocytosis. PLoS ONE 7, e42199.Google Scholar
Dlouhy, A. C. and Outten, C. E. (2013). The iron metallome in eukaryotic organisms. Metal Ions in Life Sciences 12, 241–278.CrossRefGoogle ScholarPubMed
Donovan, A., Brownlie, A., Zhou, Y., Shepard, J., Pratt, S. J., Moynihan, J., Paw, B. H., Drejer, A., Barut, B., Zapata, A., Law, T. C., Brugnara, C., Lux, S. E., Pinkus, G. S., Pinkus, J. L., Kingsley, P. D., Palis, J., Fleming, M. D., Andrews, N. C. and Zon, L. I. (2000). Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781.CrossRefGoogle ScholarPubMed
Drakesmith, H. and Prentice, A. M. (2012). Hepcidin and the iron-infection axis. Science 338, 768–772.Google Scholar
Duffy, S. P., Shing, J., Saraon, P., Berger, L. C., Eiden, M. V., Wilde, A. and Tailor, C. S. (2010). The Fowler syndrome-associated protein FLVCR2 is an importer of heme. Molecular and Cellular Biology 30, 5318–5324.Google Scholar
Eisenstein, R. S., Garcia-Mayol, D., Pettingell, W. and Munro, H. N. (1991). Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proceedings of the National Academy of Sciences of the United States of America 88, 688–692.Google Scholar
El Hage Chahine, J. M., Hemadi, M. and Ha-Duong, N. T. (2012). Uptake and release of metal ions by transferrin and interaction with receptor 1. Biochimica et Biophysica Acta 1820, 334–347.CrossRefGoogle ScholarPubMed
Fischer, R., Debbabi, H., Dubarry, M., Boyaka, P. and Tome, D. (2006). Regulation of physiological and pathological Th1 and Th2 responses by lactoferrin. Biochemistry and Cell Biology 84, 303–311.CrossRefGoogle ScholarPubMed
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. The Journal of Biological Chemistry 286, 23266–23279.Google Scholar
Flannery, A. R., Renberg, R. L. and Andrews, N. W. (2013). Pathways of iron acquisition and utilization in Leishmania . Current Opinion in Microbiology 16, 716–721.Google Scholar
Francisco, A. F., de Abreu Vieira, P. M., Arantes, J. M., Pedrosa, M. L., Martins, H. R., Silva, M., Veloso, V. M., de Lana, M., Bahia, M. T., Tafuri, W. L. and Carneiro, C. M. (2008). Trypanosoma cruzi: effect of benznidazole therapy combined with the iron chelator desferrioxamine in infected mice. Experimental Parasitology 120, 314–319.Google Scholar
Ganz, T. and Nemeth, E. (2012). Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harbor Perspectives in Medicine 2, a011668.Google Scholar
Gozzelino, R. and Arosio, P. (2016). Iron homeostasis in health and disease. International Journal of Molecular Sciences 17, 130.CrossRefGoogle ScholarPubMed
Gozzelino, R. and Soares, M. P. (2014). Coupling heme and iron metabolism via ferritin H chain. Antioxidants & Redox Signaling 20, 1754–1769.Google Scholar
Graham, R. M., Chua, A. C., Herbison, C. E., Olynyk, J. K. and Trinder, D. (2007). Liver iron transport. World Journal of Gastroenterology 13, 4725–4736.Google Scholar
Haider, A., Olszanecki, R., Gryglewski, R., Schwartzman, M. L., Lianos, E., Kappas, A., Nasjletti, A. and Abraham, N. G. (2002). Regulation of cyclooxygenase by the heme–heme oxygenase system in microvessel endothelial cells. The Journal of Pharmacology and Experimental Therapeutics 300, 188–194.Google Scholar
Haley, K. P. and Skaar, E. P. (2012). A battle for iron: host sequestration and Staphylococcus aureus acquisition. Microbes and Infection 14, 217–227.CrossRefGoogle ScholarPubMed
Harris, W. R. (2012). Anion binding properties of the transferrins. Implications for function. Biochimica et Biophysica Acta 1820, 348–361.Google Scholar
Harrison, P. M. and Arosio, P. (1996). The ferritins: molecular properties, iron storage function and cellular regulation. Biochimica et Biophysica Acta 1275, 161–203.Google Scholar
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. Journal of Experimental Medicine 203, 2363–2375.Google Scholar
Huynh, C., Yuan, X., Miguel, D. C., Renberg, R. L., Protchenko, O., Philpott, C. C., Hamza, I. and Andrews, N. W. (2012). Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathogens 8, e1002795.Google Scholar
Hvidberg, V., Maniecki, M. B., Jacobsen, C., Hojrup, P., Moller, H. J. and Moestrup, S. K. (2005). Identification of the receptor scavenging hemopexin–heme complexes. Blood 106, 2572–2579.Google Scholar
Ibrahim, A. S., Gebermariam, T., Fu, Y., Lin, L., Husseiny, M. I., French, S. W., Schwartz, J., Skory, C. D., Edwards, J. E. Jr. and Spellberg, B. J. (2007). The iron chelator deferasirox protects mice from mucormycosis through iron starvation. Journal of Clinical Investigation 117, 2649–2657.Google Scholar
Jabado, N., Jankowski, A., Dougaparsad, S., Picard, V., Grinstein, S. and Gros, P. (2000). Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. The Journal of Experimental Medicine 192, 1237–1248.Google Scholar
Kaye, P. and Scott, P. (2011). Leishmaniasis: complexity at the host-pathogen interface. Nature Reviews Microbiology 9, 604–615.Google Scholar
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. Proceedings of the National Academy of Sciences of the United States of America 102, 1324–1328.Google Scholar
Korolnek, T. and Hamza, I. (2015). Macrophages and iron trafficking at the birth and death of red cells. Blood 125, 2893–2897.Google Scholar
Kosman, D. J. (2010). Redox cycling in iron uptake, efflux, and trafficking. Journal of Biological Chemistry 285, 26729–26735.Google Scholar
Krause, A., Neitz, S., Magert, H. J., Schulz, A., Forssmann, W. G., Schulz-Knappe, P. and Adermann, K. (2000). LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Letters 480, 147–150.Google Scholar
Krishnamurthy, G., Vikram, R., Singh, S. B., Patel, N., Agarwal, S., Mukhopadhyay, G., Basu, S. K. and Mukhopadhyay, A. (2005). Hemoglobin receptor in Leishmania is a hexokinase located in the flagellar pocket. Journal of Biological Chemistry 280, 5884–5891.Google Scholar
Kristiansen, M., Graversen, J. H., Jacobsen, C., Sonne, O., Hoffman, H. J., Law, S. K. and Moestrup, S. K. (2001). Identification of the haemoglobin scavenger receptor. Nature 409, 198–201.Google Scholar
Lemesre, J. L., Sereno, D., Daulouede, S., Veyret, B., Brajon, N. and Vincendeau, P. (1997). Leishmania spp.: nitric oxide-mediated metabolic inhibition of promastigote and axenically grown amastigote forms. Experimental Parasitology 86, 58–68.CrossRefGoogle ScholarPubMed
Linder, M. C. (2013). Mobilization of stored iron in mammals: a review. Nutrients 5, 4022–4050.Google Scholar
Lodge, R. and Descoteaux, A. (2005). Leishmania donovani promastigotes induce periphagosomal F-actin accumulation through retention of the GTPase Cdc42. Cellular Microbiology 7, 1647–1658.CrossRefGoogle ScholarPubMed
Lodge, R., Diallo, T. O. and Descoteaux, A. (2006). Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane. Cellular Microbiology 8, 1922–1931.CrossRefGoogle ScholarPubMed
Long, S., Jirku, M., Mach, J., Ginger, M. L., Sutak, R., Richardson, D., Tachezy, J. and Lukes, J. (2008). Ancestral roles of eukaryotic frataxin: mitochondrial frataxin function and heterologous expression of hydrogenosomal Trichomonas homologues in trypanosomes. Molecular Microbiology 69, 94–109.CrossRefGoogle ScholarPubMed
Loreal, O., Cavey, T., Bardou-Jacquet, E., Guggenbuhl, P., Ropert, M. and Brissot, P. (2014). Iron, hepcidin, and the metal connection. Frontiers in Pharmacology 5, 128.Google Scholar
Mach, B., Steimle, V., Martinez-Soria, E. and Reith, W. (1996). Regulation of MHC class II genes: lessons from a disease. Annual Review of Immunology 14, 301–331.Google Scholar
Mach, J., Tachezy, J. and Sutak, R. (2013). Efficient iron uptake via a reductive mechanism in procyclic Trypanosoma brucei . Journal of Parasitology 99, 363–364.Google Scholar
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. Experimental Parasitology 127, 719–723.CrossRefGoogle ScholarPubMed
Martinez-Garcia, M., Campos-Salinas, J., Cabello-Donayre, M., Pineda-Molina, E., Galvez, F. J., Orrego, L. M., Sanchez-Canete, M. P., Malagarie-Cazenave, S., Koeller, D. M. and Perez-Victoria, J. M. (2016). LmABCB3, an atypical mitochondrial ABC transporter essential for Leishmania major virulence, acts in heme and cytosolic iron/sulfur clusters biogenesis. Parasites & Vectors 9, 7.Google Scholar
Mastroeni, P., Vazquez-Torres, A., Fang, F. C., Xu, Y., Khan, S., Hormaeche, C. E. and Dougan, G. (2000). Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo . Journal of Experimental Medicine 192, 237–248.Google Scholar
Matheoud, D., Moradin, N., Bellemare-Pelletier, A., Shio, M. T., Hong, W. J., Olivier, M., Gagnon, E., Desjardins, M. and Descoteaux, A. (2013). Leishmania evades host immunity by inhibiting antigen cross-presentation through direct cleavage of the SNARE VAMP8. Cell Host & Microbe 14, 15–25.Google Scholar
McCall, L. I., Zhang, W. W. and Matlashewski, G. (2013). Determinants for the development of visceral leishmaniasis disease. PLoS Pathogens 9, e1003053.Google Scholar
McKie, A. T., Barrow, D., Latunde-Dada, G. O., Rolfs, A., Sager, G., Mudaly, E., Mudaly, M., Richardson, C., Barlow, D., Bomford, A., Peters, T. J., Raja, K. B., Shirali, S., Hediger, M. A., Farzaneh, F. and Simpson, R. J. (2001). An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759.Google Scholar
Meehan, H. A., Lundberg, R. A. and Connell, G. J. (2000). A trypanosomatid protein specifically interacts with a mammalian iron-responsive element. Parasitology Research 86, 109–114.Google Scholar
Mencacci, A., Cenci, E., Boelaert, J. R., Bucci, P., Mosci, P., Fe d'Ostiani, C., Bistoni, F. and Romani, L. (1997). Iron overload alters innate and T helper cell responses to Candida albicans in mice. The Journal of Infectious Diseases 175, 1467–1476.Google Scholar
Miguel, D. C., Flannery, A. R., Mittra, B. and Andrews, N. W. (2013). Heme uptake mediated by LHR1 is essential for Leishmania amazonensis virulence. Infection and Immunity 81, 3620–3626.Google Scholar
Mittra, B. and Andrews, N. W. (2013). IRONy OF FATE: role of iron-mediated ROS in Leishmania differentiation. Trends in Parasitology 29, 489–496.Google Scholar
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. Journal of Experimental Medicine 210, 401–416.Google Scholar
Mittra, B., Laranjeira-Silva, M. F., Perrone Bezerra de Menezes, J., Jensen, J., Michailowsky, V. and Andrews, N. W. (2016). A Trypanosomatid iron transporter that regulates mitochondrial function is required for Leishmania amazonensis virulence. PLoS Pathogens 12, e1005340.Google Scholar
Morgan, E. H. and Oates, P. S. (2002). Mechanisms and regulation of intestinal iron absorption. Blood Cells, Molecules & Diseases 29, 384–399.Google Scholar
Murray, H. W. (1981). Susceptibility of Leishmania to oxygen intermediates and killing by normal macrophages. Journal of Experimental Medicine 153, 1302–1315.Google Scholar
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. Infection and Immunity 59, 4684–4686.Google Scholar
Musci, G., Polticelli, F. and Bonaccorsi di Patti, M. C. (2014). Ceruloplasmin–ferroportin system of iron traffic in vertebrates. World Journal of Biological Chemistry 5, 204–215.Google Scholar
Nairz, M., Schroll, A., Sonnweber, T. and Weiss, G. (2010). The struggle for iron – a metal at the host-pathogen interface. Cellular Microbiology 12, 1691–1702.CrossRefGoogle Scholar
Nairz, M., Schleicher, U., Schroll, A., Sonnweber, T., Theurl, I., Ludwiczek, S., Talasz, H., Brandacher, G., Moser, P. L., Muckenthaler, M. U., Fang, F. C., Bogdan, C. and Weiss, G. (2013). Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. Journal of Experimental Medicine 210, 855–873.Google Scholar
Nathan, C. and Shiloh, M. U. (2000). Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proceedings of the National Academy of Sciences of the United States of America 97, 8841–8848.Google Scholar
Nathan, C. F., Murray, H. W., Wiebe, M. E. and Rubin, B. Y. (1983). Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. Journal of Experimental Medicine 158, 670–689.CrossRefGoogle ScholarPubMed
Nemeth, E., Valore, E. V., Territo, M., Schiller, G., Lichtenstein, A. and Ganz, T. (2003). Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101, 2461–2463.Google Scholar
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K. and Ganz, T. (2004). IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Journal of Clinical Investigation 113, 1271–1276.Google Scholar
Nicolas, G., Viatte, L., Bennoun, M., Beaumont, C., Kahn, A. and Vaulont, S. (2002). Hepcidin, a new iron regulatory peptide. Blood cells, Molecules & Diseases 29, 327–335.Google Scholar
Oexle, H., Kaser, A., Most, J., Bellmann-Weiler, R., Werner, E. R., Werner-Felmayer, G. and Weiss, G. (2003). Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells. Journal of Leukocyte Biology 74, 287–294.Google Scholar
Ohgami, R. S., Campagna, D. R., Greer, E. L., Antiochos, B., McDonald, A., Chen, J., Sharp, J. J., Fujiwara, Y., Barker, J. E. and Fleming, M. D. (2005). Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nature Genetics 37, 1264–1269.CrossRefGoogle ScholarPubMed
Ohgami, R. S., Campagna, D. R., McDonald, A. and Fleming, M. D. (2006). The Steap proteins are metalloreductases. Blood 108, 1388–1394.Google Scholar
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. Impact of interferon-gamma and hemochromatosis. Journal of Biological Chemistry 277, 49727–49734.Google Scholar
Park, C. H., Valore, E. V., Waring, A. J. and Ganz, T. (2001). Hepcidin, a urinary antimicrobial peptide synthesized in the liver. Journal of Biological Chemistry 276, 7806–7810.Google Scholar
Patel, N., Singh, S. B., Basu, S. K. and Mukhopadhyay, A. (2008). Leishmania requires Rab7-mediated degradation of endocytosed hemoglobin for their growth. Proceedings of the National Academy of Sciences of the United States of America 105, 3980–3985.Google Scholar
Peyssonnaux, C., Zinkernagel, A. S., Datta, V., Lauth, X., Johnson, R. S. and Nizet, V. (2006). TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107, 3727–3732.Google Scholar
Phan, I. Q., Davies, D. R., Moretti, N. S., Shanmugam, D., Cestari, I., Anupama, A., Fairman, J. W., Edwards, T. E., Stuart, K., Schenkman, S. and Myler, P. J. (2015). Iron superoxide dismutases in eukaryotic pathogens: new insights from Apicomplexa and Trypanosoma structures. Acta crystallographica. Section F, Structural Biology Communications 71, 615–621.Google Scholar
Qiu, A., Jansen, M., Sakaris, A., Min, S. H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M. H. and Goldman, I. D. (2006). Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917–928.Google Scholar
Rajagopal, A., Rao, A. U., Amigo, J., Tian, M., Upadhyay, S. K., Hall, C., Uhm, S., Mathew, M. K., Fleming, M. D., Paw, B. H., Krause, M. and Hamza, I. (2008). Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 453, 1127–1131.CrossRefGoogle ScholarPubMed
Renberg, R. L., Yuan, X., Samuel, T. K., Miguel, D. C., Hamza, I., Andrews, N. W. and Flannery, A. R. (2015). The heme transport capacity of LHR1 determines the extent of virulence in Leishmania amazonensis . PLoS Neglected Tropical Diseases 9, e0003804.Google Scholar
Reyes-Lopez, M., Pina-Vazquez, C. and Serrano-Luna, J. (2015). Transferrin: endocytosis and cell signaling in parasitic protozoa. BioMed Research International 2015, 641392.Google Scholar
Rouault, T. A. and Tong, W. H. (2008). Iron–sulfur cluster biogenesis and human disease. Trends in Genetics 24, 398–407.Google Scholar
Rouzer, C. A. and Marnett, L. J. (2009). Cyclooxygenases: structural and functional insights. Journal of Lipid Research 50 (Suppl.), S29–S34.CrossRefGoogle ScholarPubMed
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. Veterinary Research 39, 36.Google Scholar
Segovia, M., Navarro, A. and Artero, J. M. (1989). The effect of liposome-entrapped desferrioxamine on Leishmania donovani in vitro . Annals of Tropical Medicine and Parasitology 83, 357–360.Google Scholar
Sen, G., Mukhopadhyay, S., Ray, M. and Biswas, T. (2008). Quercetin interferes with iron metabolism in Leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity. The Journal of Antimicrobial Chemotherapy 61, 1066–1075.Google Scholar
Shayeghi, M., Latunde-Dada, G. O., Oakhill, J. S., Laftah, A. H., Takeuchi, K., Halliday, N., Khan, Y., Warley, A., McCann, F. E., Hider, R. C., Frazer, D. M., Anderson, G. J., Vulpe, C. D., Simpson, R. J. and McKie, A. T. (2005). Identification of an intestinal heme transporter. Cell 122, 789–801.Google Scholar
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.Google Scholar
Singh, S. B., Tandon, R., Krishnamurthy, G., Vikram, R., Sharma, N., Basu, S. K. and Mukhopadhyay, A. (2003). Rab5-mediated endosome-endosome fusion regulates hemoglobin endocytosis in Leishmania donovani . EMBO Journal 22, 5712–5722.Google Scholar
Soteriadou, K., Papavassiliou, P., Voyiatzaki, C. and Boelaert, J. (1995). Effect of iron chelation on the in-vitro growth of Leishmania promastigotes . Journal of Antimicrobial Chemotherapy 35, 23–29.Google Scholar
Taille, C., El-Benna, J., Lanone, S., Dang, M. C., Ogier-Denis, E., Aubier, M. and Boczkowski, J. (2004). Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability. Journal of Biological Chemistry 279, 28681–28688.Google Scholar
Taylor, M. C. and Kelly, J. M. (2010). Iron metabolism in trypanosomatids, and its crucial role in infection. Parasitology 137, 899–917.Google Scholar
Torti, F. M. and Torti, S. V. (2002). Regulation of ferritin genes and protein. Blood 99, 3505–3516.CrossRefGoogle ScholarPubMed
Tripodi, K. E., Menendez Bravo, S. M. and Cricco, J. A. (2011). Role of heme and heme-proteins in trypanosomatid essential metabolic pathways. Enzyme Research 2011, 873230.CrossRefGoogle ScholarPubMed
Vale-Costa, S., Gomes-Pereira, S., Teixeira, C. M., Rosa, G., Rodrigues, P. N., Tomas, A., Appelberg, R. and Gomes, M. S. (2013). Iron overload favors the elimination of Leishmania infantum from mouse tissues through interaction with reactive oxygen and nitrogen species. PLoS Neglected Tropical Diseases 7, e2061.Google Scholar
van Crevel, R., Parwati, I., Sahiratmadja, E., Marzuki, S., Ottenhoff, T. H., Netea, M. G., van der Ven, A., Nelwan, R. H., van der Meer, J. W., Alisjahbana, B. and van de Vosse, E. (2009). Infection with Mycobacterium tuberculosis Beijing genotype strains is associated with polymorphisms in SLC11A1/NRAMP1 in Indonesian patients with tuberculosis. Journal of Infectious Diseases 200, 1671–1674.Google Scholar
Vazquez-Torres, A., Jones-Carson, J., Mastroeni, P., Ischiropoulos, H. and Fang, F. C. (2000). Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro . Journal of Experimental Medicine 192, 227–236.Google Scholar
Vidal, S., Tremblay, M. L., Govoni, G., Gauthier, S., Sebastiani, G., Malo, D., Skamene, E., Olivier, M., Jothy, S. and Gros, P. (1995). The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. Journal of Experimental Medicine 182, 655–666.Google Scholar
Vinet, A. F., Fukuda, M., Turco, S. J. and Descoteaux, A. (2009). The Leishmania donovani lipophosphoglycan excludes the vesicular proton-ATPase from phagosomes by impairing the recruitment of synaptotagmin V. PLoS Pathogens 5, e1000628.Google Scholar
Voyiatzaki, C. S. and Soteriadou, K. P. (1992). Identification and isolation of the Leishmania transferrin receptor. Journal of Biological Chemistry 267, 9112–9117.Google Scholar
Wang, L., Johnson, E. E., Shi, H. N., Walker, W. A., Wessling-Resnick, M. and Cherayil, B. J. (2008). Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. Journal of Immunology 181, 2723–2731.Google Scholar
Wang, L., Harrington, L., Trebicka, E., Shi, H. N., Kagan, J. C., Hong, C. C., Lin, H. Y., Babitt, J. L. and Cherayil, B. J. (2009). Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. Journal of Clinical Investigation 119, 3322–3328.Google Scholar
Ward, P. P., Uribe-Luna, S. and Conneely, O. M. (2002). Lactoferrin and host defense. Biochemistry and Cell Biology 80, 95–102.Google Scholar
Weiss, G. (2002). Iron and immunity: a double-edged sword. European Journal of Clinical Investigation 32 (Suppl. 1), 70–78.Google Scholar
Weiss, G. (2005). Modification of iron regulation by the inflammatory response. Best Practice & Research Clinical Haematology 18, 183–201.Google Scholar
Weiss, G., Fuchs, D., Hausen, A., Reibnegger, G., Werner, E. R., Werner-Felmayer, G. and Wachter, H. (1992). Iron modulates interferon-gamma effects in the human myelomonocytic cell line THP-1. Experimental Hematology 20, 605–610.Google Scholar
Wessling-Resnick, M. (2000). Iron transport. Annual Review of Nutrition 20, 129–151.Google Scholar
White, C., Yuan, X., Schmidt, P. J., Bresciani, E., Samuel, T. K., Campagna, D., Hall, C., Bishop, K., Calicchio, M. L., Lapierre, A., Ward, D. M., Liu, P., Fleming, M. D. and Hamza, I. (2013). HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cellular Metabolism 17, 261–270.Google Scholar
Wilson, M. E., Lewis, T. S., Miller, M. A., McCormick, M. L. and Britigan, B. E. (2002). Leishmania chagasi: uptake of iron bound to lactoferrin or transferrin requires an iron reductase. Experimental Parasitology 100, 196–207.Google Scholar
Zhong, W., Lafuse, W. P. and Zwilling, B. S. (2001). Infection with Mycobacterium avium differentially regulates the expression of iron transport protein mRNA in murine peritoneal macrophages. Infection and Immunity 69, 6618–6624.Google Scholar
Zwilling, B. S., Kuhn, D. E., Wikoff, L., Brown, D. and Lafuse, W. (1999). Role of iron in Nramp1-mediated inhibition of mycobacterial growth. Infection and Immunity 67, 1386–1392.Google Scholar