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Cited by 51Iron Metabolism and DisordersBacterial Genetics and BiotechnologyMicrobial infections and disease research

Strategies of intracellular pathogens for obtaining iron from the environment

Open access
Leon-Sicairos, Nidia, Reyes-Cortes, Ruth, Guadrón-Llanos, Alma M., Madueña-Molina, Jesús, Leon-Sicairos, Claudia, Canizalez-Román, Adrian·2015·BioMed Research International
DOI 10.1155/2015/476534PMC PMC4450229
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Abstract

Most microorganisms are destroyed by the host tissues through processes that usually involve phagocytosis and lysosomal disruption. However, some organisms, called intracellular pathogens, are capable of avoiding destruction by growing inside macrophages or other cells. During infection with intracellular pathogenic microorganisms, the element iron is required by both the host cell and the pathogen that inhabits the host cell. This minireview focuses on how intracellular pathogens use multiple strategies to obtain nutritional iron from the intracellular environment in order to use this element for replication. Additionally, the implications of these mechanisms for iron acquisition in the pathogen-host relationship are discussed.

AI snapshot

Written from the paper’s full text.

TL;DR

This minireview describes how intracellular pathogens obtain iron from host proteins and intracellular compartments, emphasizing siderophore, heme, and transferrin/lactoferrin receptor strategies. It argues that iron acquisition is central to intracellular survival and virulence, while noting that many mechanisms and in vivo roles remain unresolved.

Key findings

  • Host iron is tightly sequestered: the human body contains 3–5 g Fe, approximately 75% in hemoglobin and other iron-bound proteins and approximately 25% in plasma bound to transferrin; heme iron contributes about 10–15% of total Fe intake in western populations. Free extracellular iron is virtually absent, so intracellular pathogens must compete for host iron sources.
  • Intracellular pathogens use three main categories of iron acquisition: siderophore-based systems, heme acquisition systems, and transferrin/lactoferrin receptors. Phagosome acidification releases Fe from transferrin, and some pathogens recruit TfR1 and ferritin to pathogen-containing vacuoles.
  • Pathogen-specific examples include Francisella tularensis using TfR1, ferrireductases, DMT-1, IRPs, FupA, and FslE; Salmonella using enterobactin/salmochelin, Feo, SitABCD, and four ferritins (Bfr, FtnA, FtnB, Dps); Mycobacterium using mycobactins/carboxymycobactins, IrtAB, ESX-3, and Fur/IdeR regulation; and Candida albicans using Rbt5/Hmx1, Als3, and Sit1, with ferritin binding 4500 Fe atoms.
  • Host macrophages limit iron availability via SLC11A1 and ferroportin, while pathogen iron acquisition is regulated by Fur, IdeR, IRPs, and other regulators. Iron deprivation reduces pathogenicity of M. tuberculosis, C. burnetii, L. pneumophila, and S. typhimurium.

Methods

  • Narrative minireview; no primary data, sample, or systematic analysis are reported.
  • The paper synthesizes published literature on iron metabolism and specific intracellular pathogens, including bacteria, fungi, and protozoa.

Limitations

  • Stated: the exact role of Fe acquisition systems in vivo and their effects on pathogenic virulence remain to be determined; several mechanisms are undetermined or speculative, including F. tularensis lactoferrin use, C. neoformans liberation of Fe from transferrin/hemoglobin, T. brucei lysosomal Fe transfer, and modulation of Fe regulatory proteins by intracellular pathogens.
  • Evident: as a narrative minireview, it does not describe systematic search, inclusion criteria, or quality appraisal, and it presents no primary experimental validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1155/2015/476534

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 143 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    During infection with intracellular pathogenic microorganisms, iron is required by both the host cell and the pathogen that inhabits the host cell.

    “During infection with intracellular pathogenic microorganisms, the element iron is required by both the host cell and the pathogen that inhabits the host cell.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Pan X. Tamilselvam B. Hansen E. J. Daefler S. Modulation of iron homeostasis in macrophages by bacterial intracellular pathogens BMC Microbiology 2010 10, article 64 10.1186/1471-2180-10-64 2-s2.0-77949543589 PMC2838877 20184753 source

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  • Interpretationreasoning

    Taken together, these factors ensure that vertebrate tissue is virtually devoid of free iron.

    “Taken together, these factors ensure that vertebrate tissue is virtually devoid of free iron [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Skaar E. P. The battle for iron between bacterial pathogens and their vertebrate hosts PLoS Pathogens 2010 6 8 e1000949 10.1371/journal.ppat.1000949 2-s2.0-77958143617 PMC2920840 20711357 source

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  • Premisecitation

    Macrophages require Fe as a cofactor for the execution of important antimicrobial effector mechanisms, including the NADPH-dependent oxidative burst and the production of nitrogen radicals catalyzed by inducible nitric oxide synthase.

    “Macrophages require Fe as a cofactor for the execution of important antimicrobial effector mechanisms, including the NADPH- (nicotinamide adenine dinucleotide phosphate-oxidase-) dependent oxidative burst and the production of nitrogen radicals catalyzed by the inducible nitric oxide synthase [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Barton C. H. Biggs T. E. Baker S. T. Bowen H. Atkinson P. G. P. Nramp 1: a link between intracellular iron transport and innate resistance to intracellular pathogens Journal of Leukocyte Biology 1999 66 5 757 762 2-s2.0-0032590006 10577506 source

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  • Interpretationreasoning

    Once inside host cells, bacteria must utilize specialized mechanisms to protect themselves from the harsh environment of the lysosomal enzymes encountered within the cells.

    “Moreover, once inside host cells, bacteria must utilize specialized mechanisms to protect themselves from the harsh environment of the lysosomal enzymes encountered within the cells.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    If ingested bacteria have no intracellular survival mechanisms, the bacteria-containing phagosomes fuse with the lysosomal compartment, and bacteria are digested within 15-30 min.

    “If the ingested bacteria have no intracellular survival mechanisms, the bacteria-containing phagosomes fuse with the lysosomal compartment, and bacteria are digested within 15–30 min.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Theriot J. A. The cell biology of infection by intracellular bacterial pathogens Annual Review of Cell and Developmental Biology 1995 11 1 213 239 10.1146/annurev.cb.11.110195.001241 8689557 source

      Not checked in the free run.

    • cites [9] Harley V. S. Drasar B. S. Forrest B. Krahn B. Tovey G. Invasion strategies and intracellular growth of bacterial pathogens Biochemical Society Transactions 1989 17 6 p. 1118 2-s2.0-0024806730 2628104

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  • May combine two claims. 51
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    In a healthy individual, Fe is largely intracellular, sequestered within Ft or as a cofactor of heme complexed to Hb within erythrocytes.

    “In a healthy individual Fe is largely intracellular, sequestered within Ft or as a cofactor of heme complexed to Hb within erythrocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Skaar E. P. The battle for iron between bacterial pathogens and their vertebrate hosts PLoS Pathogens 2010 6 8 e1000949 10.1371/journal.ppat.1000949 2-s2.0-77958143617 PMC2920840 20711357 source

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    Premisecitation

    Bacteria that can enter and survive within eukaryotic cells are shielded from humoral antibodies and can be eliminated only by a cellular immune response.

    “Bacteria that can enter and survive within eukaryotic cells are shielded from humoral antibodies and can be eliminated only by a cellular immune response [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Fredlund J. Enninga J. Cytoplasmic access by intracellular bacterial pathogens Trends in Microbiology 2014 22 3 128 137 10.1016/j.tim.2014.01.003 2-s2.0-84896709457 24530174

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Obligate intracellular parasites cannot reproduce outside their host cell.

    “Obligate intracellular parasites cannot reproduce outside their host cell, which means that the parasite's reproduction is entirely reliant on intracellular resources.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Khan N. Gowthaman U. Pahari S. Agrewala J. N. Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!! PLoS Pathogens 2012 8 6 e1002676 10.1371/journal.ppat.1002676 2-s2.0-84864075069 PMC3375268 22719245

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  • Classified as probably not a substantial claim.

    Premisenone given

    Intracellular pathogens are capable of avoiding destruction by growing inside macrophages or other cells.

    “However, some organisms, called intracellular pathogens, are capable of avoiding destruction by growing inside macrophages or other cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hb or heme released as a result of natural erythrocyte lysis is captured by haptoglobin and hemopexin, respectively.

    “Hb or heme that is released as a result of natural erythrocyte lysis is captured by haptoglobin and hemopexin, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Skaar E. P. The battle for iron between bacterial pathogens and their vertebrate hosts PLoS Pathogens 2010 6 8 e1000949 10.1371/journal.ppat.1000949 2-s2.0-77958143617 PMC2920840 20711357 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Facultative intracellular parasites are capable of living and reproducing either inside or outside host cells.

    “Facultative intracellular parasites, for example, bacteria such as Francisella tularensis, Listeria monocytogenes, Salmonella typhi, Mycobacterium spp., and Neisseria meningitidis, are capable of living and reproducing either inside or outside host cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Casadevall A. Evolution of intracellular pathogens Annual Review of Microbiology 2008 62 19 33 10.1146/annurev.micro.61.080706.093305 2-s2.0-53849139142 18785836

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  • May combine two claims.

    Interpretationreasoning

    To grow, intracellular pathogens need nutrients such as iron, which might be scarce in the cell because it is usually retained or stored by proteins.

    “To grow, intracellular pathogens need nutrients such as the iron, that might be scarce in the cell, because this is usually retained or stored by proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The transferrin-binding proteins in N. meningitidis are TbpA (98 kDa) and TbpB (68 kDa).

    “The proteins that bound transferrin were TbpA (formerly Tbp1), which is 98 kDa, and TbpB (formerly Tbp2), which is 68 kDa [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Criado M. T. Pintor M. Ferreiros C. M. Iron uptake by Neisseria meningitidis Research in Microbiology 1993 144 1 77 82 10.1016/0923-2508(93)90217-p 2-s2.0-0027535753 8327785

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  • May combine two claims.

    Premisenone given

    L. pneumophila has developed multiple Fe acquisition mechanisms: ira AB locus, ccm genes, frgA, legiobactin siderophores, and two internal ferric reductases.

    “To occupy its intracellular niche, this pathogen has developed multiple Fe acquisition mechanisms: the ira AB locus, which encodes a transporter for Fe-loaded peptides; the cytochrome c maturation ccm genes; the Fe-regulated frgA, whose product is homologous to aerobactin synthetases; legiobactin siderophores; and two internal ferric reductases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    TbpA is found in all meningococcal strains.

    “TbpA can be found in all strains.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sequence analysis predicts Lpp_2867 is a membrane protein involved directly or indirectly in Fe2+ transport and is a virulence factor.

    “A sequence analysis predicts that Lpp_2867 is a membrane protein involved directly or indirectly in Fe2+ transport and is also a virulence factor [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Portier E. Zheng H. Sahr T. IroT/mavN, a new iron-regulated gene involved in Legionella pneumophila virulence against amoebae and macrophages Environmental Microbiology 2014 10.1111/1462-2920.12604 PMC4672373 25141909

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    Premisecitation

    Siderophore Fe uptake systems, heme transporters, and Fe3+ and Fe2+ transport systems are present in Shigella, and genes encoding some spread by horizontal transmission.

    “Siderophore Fe uptake systems, heme transporters, and Fe3+ and Fe2+ transport systems are present in these bacteria, and the genes encoding some of these systems appear to have spread among the Shigella species by horizontal transmission [50, 51].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Payne S. M. Iron and virulence in Shigella Molecular Microbiology 1989 3 9 1301 1306 2-s2.0-0024469919 10.1111/j.1365-2958.1989.tb00281.x 2677608

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    • cites [51] Fisher C. R. Davies N. M. L. L. Wyckoff E. E. Feng Z. Oaks E. V. Payne S. M. Genetics and virulence association of the Shigella flexneri sit iron transport system Infection and Immunity 2009 77 5 1992 1999 10.1128/iai.00064-09 2-s2.0-65449175727 19289511 PMC2681762

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  • May combine two claims.

    Premisecitation

    Siderophores are small ferric iron chelators that bind with extremely high affinity (iron formation constants Kd range from 10−20 to 10−50 M), some of which can extract iron from Tf and Lf.

    “Siderophores are small ferric iron chelators that bind with extremely high affinity (iron formation constants K d range from 10−20 to 10−50 M), some of which can extract iron from Tf and Lf [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Skaar E. P. The battle for iron between bacterial pathogens and their vertebrate hosts PLoS Pathogens 2010 6 8 e1000949 10.1371/journal.ppat.1000949 2-s2.0-77958143617 PMC2920840 20711357 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fe is essential for growth of Shigella and plays an important role in regulation of metabolic processes and virulence determinants.

    “Fe is not only essential for the growth of Shigella but also plays an important role in the regulation of metabolic processes and virulence determinants in Shigella.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Payne S. M. Wyckoff E. E. Murphy E. R. Oglesby A. G. Boulette M. L. Davies N. M. L. Iron and pathogenesis of Shigella: iron acquisition in the intracellular environment BioMetals 2006 19 2 173 180 10.1007/s10534-005-4577-x 2-s2.0-33646932648 16718602

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Among meningococcal isolates, TbpA molecular mass varies from 93 to 98 kDa and TbpB from 68 to 85 kDa.

    “Among different meningococcal isolates, the molecular masses of TbpA and TbpB vary, with TbpA ranging from 93 to 98 kDa and the more heterogenetic TbpB varying from 68 to 85 kDa.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In E. coli and Salmonella, FeoB is a ferrous Fe transporter and FeoA is possibly involved in Fe2+ uptake.

    “In those bacteria, FeoB has been shown to be a ferrous Fe transporter and FeoA is possibly involved in Fe2+ uptake [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Robey M. Cianciotto N. P. Legionella pneumophila feoAB promotes ferrous iron uptake and intracellular infection Infection and Immunity 2002 70 10 5659 5669 10.1128/iai.70.10.5659-5669.2002 2-s2.0-0036785675 12228295 PMC128349

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  • May combine two claims.

    Premisecitation

    ArcA and FNR regulate Shigella Fe transport gene expression as a function of oxygen tension, with sit and iuc promoters highly expressed aerobically and feo promoter most active anaerobically.

    “ArcA and FNR regulate Fe transport gene expression as a function of oxygen tension, with the sit and iuc promoters being highly expressed in aerobic conditions, while the feo Fe2+ transporter promoter is most active under anaerobic conditions [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Payne S. M. Wyckoff E. E. Murphy E. R. Oglesby A. G. Boulette M. L. Davies N. M. L. Iron and pathogenesis of Shigella: iron acquisition in the intracellular environment BioMetals 2006 19 2 173 180 10.1007/s10534-005-4577-x 2-s2.0-33646932648 16718602

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All Shigella species have both Feo and Sit systems for Fe2+ acquisition, and all have at least one siderophore-mediated system for Fe3+ transport.

    “All Shigella species have both the Feo and Sit systems for acquisition of Fe2+, and all have at least one siderophore-mediated system for transport of Fe3+ [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Runyen-Janecky L. J. Reeves S. A. Gonzales E. G. Payne S. M. Contribution of the Shigella flexneri sit, iuc, and feo iron acquisition systems to iron acquisition in vitro and in cultured cells Infection and Immunity 2003 71 4 1919 1928 10.1128/iai.71.4.1919-1928.2003 2-s2.0-0037379467 12654809 PMC152062

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  • May combine two claims.

    Premisecitation

    L. pneumophila resides in a phagosome that does not fuse with endosomes and lysosomes and is at nearly neutral pH during early intracellular life cycle.

    “L. pneumophila resides in the phagosome, although this phagosome does not fuse with endosomes and lysosomes and is at nearly neutral pH during the early stages of the intracellular life cycle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Horwitz M. A. Silverstein S. C. Legionnaires' disease bacterium (Legionella pneumophila) multiples intracellularly in human monocytes The Journal of Clinical Investigation 1980 66 3 441 450 10.1172/jci109874 2-s2.0-0018885613 7190579 PMC371671

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  • May combine two claims.

    Premisecitation

    In S. flexneri infection of cultured cells, Sit and Iuc systems support plaque formation under aerobic conditions, whereas Feo allows plaque formation anaerobically.

    “The effects of oxygen are also observed in infection of cultured cells by S. flexneri; the Sit and Iuc systems support plaque formation under aerobic conditions, whereas Feo allows plaque formation to occur anaerobically [52, 53].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Payne S. M. Wyckoff E. E. Murphy E. R. Oglesby A. G. Boulette M. L. Davies N. M. L. Iron and pathogenesis of Shigella: iron acquisition in the intracellular environment BioMetals 2006 19 2 173 180 10.1007/s10534-005-4577-x 2-s2.0-33646932648 16718602

      Not checked in the free run.

    • cites [53] Runyen-Janecky L. J. Reeves S. A. Gonzales E. G. Payne S. M. Contribution of the Shigella flexneri sit, iuc, and feo iron acquisition systems to iron acquisition in vitro and in cultured cells Infection and Immunity 2003 71 4 1919 1928 10.1128/iai.71.4.1919-1928.2003 2-s2.0-0037379467 12654809 PMC152062

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  • May combine two claims.

    Premisecitation

    Bacterial cytotoxins damage host cells, leading to the release of Ft, while hemolytic toxins from bacteria can lyse erythrocytes, liberating Hb.

    “For example, bacterial cytotoxins damage host cells, leading to the release of Ft, while hemolytic toxins from bacteria can lyse erythrocytes, liberating Hb.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Abu Kwaik Y. Bumann D. Microbial quest for food in vivo: ‘nutritional virulence’ as an emerging paradigm Cellular Microbiology 2013 15 6 882 890 10.1111/cmi.12138 2-s2.0-84877829941 23490329

      Not checked in the free run.

    • cites [21] Skaar E. P. The battle for iron between bacterial pathogens and their vertebrate hosts PLoS Pathogens 2010 6 8 e1000949 10.1371/journal.ppat.1000949 2-s2.0-77958143617 PMC2920840 20711357 source

      Not checked in the free run.

    • cites [27] Nairz M. Schroll A. Sonnweber T. Weiss G. The struggle for iron—a metal at the host-pathogen interface Cellular Microbiology 2010 12 12 1691 1702 10.1111/j.1462-5822.2010.01529.x 2-s2.0-78449290415 20964797 source

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  • May combine two claims.

    Premisecitation

    Secreted siderophores can remove Fe from Tf, Lf, or Ft, whereupon siderophore-iron complexes are recognized by cognate receptors at the bacterial surface.

    “Alternatively, secreted siderophores can remove Fe from Tf, Lf, or Ft, whereupon siderophore-iron complexes are recognized by cognate receptors at the bacterial surface.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Skaar E. P. The battle for iron between bacterial pathogens and their vertebrate hosts PLoS Pathogens 2010 6 8 e1000949 10.1371/journal.ppat.1000949 2-s2.0-77958143617 PMC2920840 20711357 source

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  • May combine two claims.

    Premisecitation

    Of the two ferric permeases in C. albicans, only Ftr1 is expressed when iron is limited, and FTR1 is essential in a murine bloodstream infection model of virulence.

    “Of the two ferric permeases, only Ftr1 is expressed when iron is limited, and FTR1 is essential in a murine bloodstream infection model of virulence [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

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  • May combine two claims.

    Premisecitation

    Expression of bfrA and bfrB is induced under Fe-rich conditions and repressed under Fe-deprived conditions.

    “Their expression is induced under Fe-rich conditions and repressed under Fe-deprived conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Genes upregulated under Fe-rich conditions include bacterioferritin and ferritin (bfrA and bfrB), catalase-peroxidase katG, and its regulator FurA.

    “Genes that are upregulated under Fe-rich conditions include bacterioferritin and ferritin (bfrA and bfrB), as they serve to store excess Fe as catalase-peroxidase, or katG and its regulator, ferric uptake regulator A (FurA) [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Yellaboina S. Ranjan S. Vindal V. Ranjan A. Comparative analysis of iron regulated genes in Mycobacteria FEBS Letters 2006 580 11 2567 2576 10.1016/j.febslet.2006.03.090 2-s2.0-33646198530 16631750

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  • May combine two claims.

    Interpretationcitation

    Als3 integrates Fe uptake and virulence functions but only in oral epithelial infection models.

    “Thus, Als3 integrates Fe uptake and virulence functions but only in oral epithelial infection models.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

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    • cites [72] Cleary I. A. Reinhard S. M. Lindsay Miller C. Candida albicans adhesin Als3p is dispensable for virulence in the mouse model of disseminated candidiasis Microbiology 2011 157 6 1806 1815 10.1099/mic.0.046326-0 2-s2.0-79958179535 21436220 PMC3167918

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    FurB is regulated by zinc and not Fe and has been correctly referred to as Zur.

    “FurB, on the other hand, was later found to be regulated by zinc and not Fe and has been correctly referred to as Zur.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    FurA, after binding ferric iron, recognizes and binds a 19-base-pair pseudopalindrome Fur Box upstream of a gene and acts as a repressor.

    “After binding ferric iron, FurA recognizes and binds to a 19-base-pair pseudopalindrome sequence of a specific DNA motif called Fur Box that is present upstream to a gene and acts as a repressor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Microvesicles play a role in Fe acquisition in M. tuberculosis and can be critical for survival in the host.

    “Consequently, the results revealed that microvesicles play a role in Fe acquisition in M. tuberculosis, and this can be critical for survival in the host.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    M. tuberculosis increases microvesicle production in response to Fe restriction, and these microvesicles contain mycobactin, which can serve as an iron donor and supports replication of Fe-starved mycobacteria.

    “On the other hand, it has been documented that M. tuberculosis increases microvesicles production in response to Fe restriction and that these microvesicles contain mycobactin, which can serve as an iron donor and supports replication of Fe-starved mycobacteria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Banerjee S. Farhana A. Ehtesham N. Z. Hasnain S. E. Iron acquisition, assimilation and regulation in mycobacteria Infection, Genetics and Evolution 2011 11 5 825 838 10.1016/j.meegid.2011.02.016 2-s2.0-79956299500 21414421

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    Premisecitation

    The polar siderophores are carboxymycobactins (released by pathogenic mycobacteria) and exochelins (released by nonpathogenic mycobacteria).

    “These are called carboxymycobactins (released by pathogenic mycobacteria) and exochelins (released by nonpathogenic mycobacteria).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Genes upregulated under Fe-deprived conditions in M. tuberculosis include siderophores, biosynthesis gene clusters mbt1 and mbt2, and Fe regulated transporters irtA, irtB, Rv2895c, and esx.

    “The genes that are upregulated under Fe-deprived conditions included those that are responsible for acquisition of Fe, such as siderophores, biosynthesis gene clusters mbt1 and mbt2, and Fe regulated transporters of siderophores irtA, irtB, Rv2895c, and esx [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Banerjee S. Farhana A. Ehtesham N. Z. Hasnain S. E. Iron acquisition, assimilation and regulation in mycobacteria Infection, Genetics and Evolution 2011 11 5 825 838 10.1016/j.meegid.2011.02.016 2-s2.0-79956299500 21414421

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    This C. burnetii protein might protect DNA from the Fenton reaction.

    “The implication is that this protein might protect DNA from the Fenton reaction [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Hicks L. D. Raghavan R. Battisti J. M. Minnick M. F. A DNA-binding peroxiredoxin of Coxiella burnetii is involved in countering oxidative stress during exponential-phase growth Journal of Bacteriology 2010 192 8 2077 2084 10.1128/jb.01324-09 2-s2.0-77950669239 20173000 PMC2849434

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  • May combine two claims.

    Premisecitation

    Failure to assemble the Fe acquisition machinery or to repress Fe uptake has deleterious effects for M. tuberculosis.

    “Recent studies have demonstrated that failure to assemble the Fe acquisition machinery or to repress Fe uptake has deleterious effects for M. tuberculosis [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Banerjee S. Farhana A. Ehtesham N. Z. Hasnain S. E. Iron acquisition, assimilation and regulation in mycobacteria Infection, Genetics and Evolution 2011 11 5 825 838 10.1016/j.meegid.2011.02.016 2-s2.0-79956299500 21414421

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Fe+3-carboxymycobactin can transfer Fe+3 to mycobactin or bring it into the cell via the iron-regulated transporter IrtAB.

    “Fe+3-carboxymycobactin can transfer Fe+3 to mycobactin or bring it into the cell via the iron-regulated transporter IrtAB.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    C. albicans utilizes Ft as an Fe source in vitro, or directly from epithelial cells in culture.

    “It has been documented that C. albicans utilizes Ft as Fe source in vitro, or directly from epithelial cells in culture.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L. monocytogenes possesses at least four mechanisms for Fe uptake: protein-bound Fe acquisition via HupDGC or Fhu, extracellular/surface-bound Fe reductases, citrate-inducible ferric citrate uptake, and siderophore/siderophore-like systems.

    “L. monocytogenes possesses at least 4 mechanisms that enable Fe uptake: (1) acquisition of protein-bound Fe that involves the HupDGC protein (for the uptake of hemin, hemoglobin), or Fhu protein (involved in the uptake of ferrichrome siderophores); inside the cell, then Fe can be bound to the Fri protein (ferritin-like) Fur regulated; (2) extracellular and/or surface-bound Fe reductases; (3) a cit”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] McLaughlin H. P. Hill C. Gahan C. G. The impact of iron on Listeria monocytogenes; inside and outside the host Current Opinion in Biotechnology 2011 22 2 194 199 10.1016/j.copbio.2010.10.005 2-s2.0-79954421029 21093251

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M. smegmatis also produces a peptidic siderophore known as exochelin, which is the predominant siderophore secreted by this mycobacterium under Fe limitation.

    “In addition to mycobactins, M. smegmatis also produces a peptidic siderophore known as exochelin, which is the predominant siderophore secreted by this mycobacterium under Fe limitation [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Banerjee S. Farhana A. Ehtesham N. Z. Hasnain S. E. Iron acquisition, assimilation and regulation in mycobacteria Infection, Genetics and Evolution 2011 11 5 825 838 10.1016/j.meegid.2011.02.016 2-s2.0-79956299500 21414421

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Free Hb or its heme/hemin ring is bound by hemoglobin receptor Rbt5 on the fungal cell surface, followed by endocytosis of Rbt5-hemoglobin complexes and release of Fe2+ by heme oxidase Hmx1.

    “Free Hb or its heme/hemin metal-porphyrin ring is bound by a hemoglobin receptor, Rbt5, on the fungal cell surface, followed by endocytosis of Rbt5-hemoglobin complexes and release of Fe2+ by the heme oxidase, Hmx1 [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Siderophores avidly bind Fe+3 and can effectively compete with host Fe binding proteins for this metal.

    “Siderophores avidly bind Fe+3 and can effectively compete with host Fe binding proteins for this metal.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C. albicans is responsible for the majority of Candida bloodstream and mucosal infections.

    “Among Candida species, C. albicans is responsible for the majority of Candida bloodstream and mucosal infections.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Mavor A. L. Thewes S. Hube B. Systemic fungal infections caused by Candida species: epidemiology, infection process and virulence attributes Current Drug Targets 2005 6 8 863 874 10.2174/138945005774912735 2-s2.0-27944505093 16375670

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The lipophilic siderophores that remain associated with the cell wall are called mycobactins, and the second class includes polar forms released into the extracellular medium.

    “The lipophilic siderophores that remain associated with the cell wall are called mycobactins, and the second class of siderophores includes polar forms that are released into the extracellular medium [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Banerjee S. Farhana A. Ehtesham N. Z. Hasnain S. E. Iron acquisition, assimilation and regulation in mycobacteria Infection, Genetics and Evolution 2011 11 5 825 838 10.1016/j.meegid.2011.02.016 2-s2.0-79956299500 21414421

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The putative transporter encoded by fxuABC may transport Fe+3-exochelin complexes.

    “The putative transporter encoded by fxuABC may transport Fe+3-exochelin complexes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    C. albicans encodes four additional homologs of Rbt5, of which Rbt51 has been demonstrated to bind hemin.

    “It has been reported that C. albicans encodes four additional homologs of Rbt5, of which Rbt51 has also been demonstrated to bind to hemin [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C. burnetii expresses a thiol-specific peroxidase (CBU0963) belonging to the atypical 2-cysteine subfamily of peroxiredoxins, also designated bacterioferritin comigratory proteins.

    “Reports have described the expression of a thiol-specific peroxidase (CBU0963) in C. burnetii that belongs to the atypical 2-cysteine subfamily of peroxiredoxins, also designated as bacterioferritin comigratory proteins (BCPs).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Hicks L. D. Raghavan R. Battisti J. M. Minnick M. F. A DNA-binding peroxiredoxin of Coxiella burnetii is involved in countering oxidative stress during exponential-phase growth Journal of Bacteriology 2010 192 8 2077 2084 10.1128/jb.01324-09 2-s2.0-77950669239 20173000 PMC2849434

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Leishmania parasites have a digenetic life cycle, alternating between promastigote in insect gut and amastigote in macrophages of mammalian hosts.

    “Leishmania parasites have a digenetic life cycle, alternating between the promastigote stage in the insect gut and the amastigote stage in macrophages of mammalian hosts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A conserved extracellular siderophore transporter domain (SITD) within Sit1 is important for the siderophore-mediated ability of C. glabrata to resist macrophage killing and is dependent on macrophage Fe status.

    “Within the Sit1 transporter, a conserved extracellular siderophore transporter domain (SITD) was identified that is important for the siderophore-mediated ability of C. glabrata to resist macrophage killing and is dependent on macrophage Fe status [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Nevitt T. Thiele D. J. Host iron withholding demands siderophore utilization for Candida glabrata to survive macrophage killing PLoS Pathogens 2011 7 3 e1001322 2-s2.0-79953283725 10.1371/journal.ppat.1001322 PMC3060170 21445236

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The high-affinity reductive Fe uptake system is required for utilization of alternate carbon sources and for growth under both in vitro Fe-limiting and in vivo conditions in C. glabrata.

    “The results revealed that the high-affinity reductive Fe uptake system is required for the utilization of alternate carbon sources and for growth under both in vitro Fe-limiting and in vivo conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Srivastava V. K. Suneetha K. J. Kaur R. A systematic analysis reveals an essential role for high-affinity iron uptake system, haemolysin and CFEM domain-containing protein in iron homoeostasis and virulence in Candida glabrata Biochemical Journal 2014 463 1 103 114 10.1042/bj20140598 24987864

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of SIT1 abolishes C. albicans virulence in a reconstituted human epithelial infection model but not in a bloodstream infection model.

    “Similar to ALS3, deletion of SIT1 abolishes C. albicans virulence in a reconstituted human epithelial infection model but not in a bloodstream infection model [69, 74].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

      Not checked in the free run.

    • cites [74] Heymann P. Gerads M. Schaller M. Dromer F. Winkelmann G. Ernst J. F. The siderophore iron transporter of Candida albicans (Sit1p/Arn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasion Infection and Immunity 2002 70 9 5246 5255 10.1128/iai.70.9.5246-5255.2002 2-s2.0-0036716474 12183576 PMC128288 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The reductive high-affinity Fe uptake system mediated by Cft1 and Cfo1 is closely associated with reduction of Fe3+ at the cell surface and is limited in the environment at neutral pH.

    “The reductive high-affinity Fe uptake system mediated by Cft1 and Cfo1 was characterized, its function was closely associated with the reduction of Fe3+ at the cell surface by the reductase activity, and it was limited in the environment at neutral pH [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Choi J. N. Kim J. Jung W. H. Lee C. H. Influence of iron regulation on the metabolome of Cryptococcus neoformans PLoS ONE 2012 7 7 e41654 2-s2.0-84864246794 10.1371/journal.pone.0041654 PMC3402442 22911836

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. glabrata, Sit1 is the sole siderophore Fe transporter and is critical for enhancing survival in the face of macrophage microbicidal activities.

    “In a study by Nevitt and Thiele (2011), Sit1 is described as the sole siderophore Fe transporter in C. glabrata, and the study demonstrates that this siderophore is critical for enhancing their survival in the face of the microbicidal activities of macrophages [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Nevitt T. Thiele D. J. Host iron withholding demands siderophore utilization for Candida glabrata to survive macrophage killing PLoS Pathogens 2011 7 3 e1001322 2-s2.0-79953283725 10.1371/journal.ppat.1001322 PMC3060170 21445236

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents.

    “Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Jung W. H. Do E. Iron acquisition in the human fungal pathogen Cryptococcus neoformans Current Opinion in Microbiology 2013 16 6 686 691 10.1016/j.mib.2013.07.008 2-s2.0-84888133477 23927895

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. neoformans is able to utilize Tf through the reductive high-affinity iron uptake system and extracellular heme by Cig1 and the ESCRT complex.

    “On the other hand, C. neoformans is able to utilize Tf through the reductive high-affinity iron uptake system and extracellular heme by Cig1 and the ESCRT complex; however, more studies should be carried out to understand how C. neoformans directly liberates Fe from Tf as well as Hb and other heme-containing proteins [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Jung W. H. Do E. Iron acquisition in the human fungal pathogen Cryptococcus neoformans Current Opinion in Microbiology 2013 16 6 686 691 10.1016/j.mib.2013.07.008 2-s2.0-84888133477 23927895

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tf can reach the lysosome-like parasitophorous vacuoles where Leishmania resides in macrophages, and it appears to function mainly as a source of Fe3+ for the sequential action of LFR1 and LIT1, which directly promote Fe2+ uptake.

    “Tf can reach the lysosome-like parasitophorous vacuoles where Leishmania resides in macrophages, but it appears to function mainly as a source of Fe3+ for the sequential action of two surface-associated parasite molecules: the Fe3+ reductase LFR1 and the LIT1 transporter, which directly promote Fe2+ uptake.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Jacques I. Andrews N. W. Huynh C. Functional characterization of LIT1, the Leishmania amazonensis ferrous iron transporter Molecular and Biochemical Parasitology 2010 170 1 28 36 10.1016/j.molbiopara.2009.12.003 2-s2.0-74249096627 20025906 PMC2815141

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of ALS3 abrogated C. albicans virulence in the oral epithelial infection model, but not in a bloodstream infection model.

    “This conclusion was obtained when deletion of ALS3 abrogated C. albicans virulence in the oral epithelial infection model, but not in a bloodstream infection model [69, 72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Kaba H. E. J. Nimtz M. Müller P. P. Bilitewski U. Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability BMC Microbiology 2013 13, article 16 10.1186/1471-2180-13-16 2-s2.0-84872681588 PMC3637358 23347662

      Not checked in the free run.

    • cites [72] Cleary I. A. Reinhard S. M. Lindsay Miller C. Candida albicans adhesin Als3p is dispensable for virulence in the mouse model of disseminated candidiasis Microbiology 2011 157 6 1806 1815 10.1099/mic.0.046326-0 2-s2.0-79958179535 21436220 PMC3167918

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The gene CIR1 shares structural and functional features with other fungal GATA-type transcription factors for iron regulation.

    “It has been suggested that the gene CIR1 (Cryptococcus iron regulator) shares structural and functional features with other fungal GATA-type transcription factors for iron regulation [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Jung W. H. Sham A. White R. Kronstad J. W. Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans PLoS Biology 2006 4 12, article e410 10.1371/journal.pbio.0040410 2-s2.0-33947503126 PMC1637126 17121456

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A mutant lacking either CFT1 or CFO1 displayed attenuation of virulence and eventually caused disease in infected mice.

    “Moreover, a mutant lacking either CFT1 or CFO1 displayed attenuation of virulence and eventually caused disease in infected mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Choi J. N. Kim J. Jung W. H. Lee C. H. Influence of iron regulation on the metabolome of Cryptococcus neoformans PLoS ONE 2012 7 7 e41654 2-s2.0-84864246794 10.1371/journal.pone.0041654 PMC3402442 22911836

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CgCcw14 and CgMam3 are essential for maintenance of intracellular Fe content, adherence to epithelial cells, and virulence in C. glabrata.

    “Further, they showed for the first time that the cysteine-rich CFEM domain-containing cell wall structural protein CgCcw14 and the putative hemolysin CgMam3 are essential for maintenance of intracellular Fe content, adherence to epithelial cells, and virulence [78].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Srivastava V. K. Suneetha K. J. Kaur R. A systematic analysis reveals an essential role for high-affinity iron uptake system, haemolysin and CFEM domain-containing protein in iron homoeostasis and virulence in Candida glabrata Biochemical Journal 2014 463 1 103 114 10.1042/bj20140598 24987864

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acidification of the phagosome permits the iron to be released from Tf, and, in this way, some pathogens can gain access to this element.

    “Acidification of the phagosome permits the iron to be released from Tf, and, in this way, some pathogens can gain access to this element [12].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Pan X. Tamilselvam B. Hansen E. J. Daefler S. Modulation of iron homeostasis in macrophages by bacterial intracellular pathogens BMC Microbiology 2010 10, article 64 10.1186/1471-2180-10-64 2-s2.0-77949543589 PMC2838877 20184753

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In times of Fe repletion, intracellular microorganisms must regulate the genes required for Fe acquisition, but this mechanism has not been fully characterized.

    “In times of Fe repletion, intracellular microorganisms must regulate the genes required for Fe acquisition, but this mechanism has not been fully characterized [45, 61].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Criado M. T. Pintor M. Ferreiros C. M. Iron uptake by Neisseria meningitidis Research in Microbiology 1993 144 1 77 82 10.1016/0923-2508(93)90217-p 2-s2.0-0027535753 8327785

      Not checked in the free run.

    • cites [61] Agranoff D. Krishna S. Metal ion transport and regulation in Mycobacterium tuberculosis Frontiers in Bioscience 2004 9 2996 3006 10.2741/1454 2-s2.0-33544471308 15353332

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two general mechanisms of Fe acquisition in intracellular parasites have been described: siderophore-mediated Fe acquisition by cognate receptors and receptor-mediated Fe acquisition from host Fe-binding proteins.

    “Two general mechanisms of Fe acquisition in intracellular parasites have been described: siderophore-mediated Fe acquisition by cognate receptors and receptor-mediated Fe acquisition from host Fe-binding proteins [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Collins H. L. The role of iron in infections with intracellular bacteria Immunology Letters 2003 85 2 193 195 10.1016/s0165-2478(02)00229-8 2-s2.0-0037460114 12527227 source

      Not checked in the free run.

61 of 61

  • The paper relies on this without support.

    Iron is not freely available in the host.

    “Because Fe is not freely available in the host, Mycobacteria must actively compete for this metal to establish an infection, but they must also carefully control Fe acquisition, as excess free Fe can be extremely toxic.”

  • The paper relies on this without support.

    L. donovani decreases the macrophage's labile Fe pool, triggering increased surface expression of transferrin receptor 1 and internalization of Tf, thus permitting continuous provision of Fe to the parasite.

    “Alternatively, L. donovani is capable of decreasing the macrophage's labile Fe pool, a process that triggers an increased surface expression of transferrin receptor 1 and internalization of Tf, thus permitting continuous provision of Fe to the parasite.”

  • The paper relies on this without support.

    The expression of ferroportin is downregulated in the spleen of L. donovani-infected mice.

    “Also, in line with these data, it has been reported that the expression of ferroportin is downregulated in the spleen of L. donovani-infected mice, which may contribute to an increased accumulation of iron inside macrophages.”

  • The paper relies on this without support.

    Tf is restricted to the lumen of the endocytic pathway and is therefore absent from the host cell cytosol, where intracellular amastigotes replicate.

    “Tf is restricted to the lumen of the endocytic pathway and is therefore absent from the host cell cytosol, where intracellular amastigotes replicate.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Candida albicans has both four and two ferric permeases

    Minor

    The same paragraph says C. albicans encodes four putative ferric permeases, then refers to only two ferric permeases without explaining the change in count.

  • Ferroportin is classified as both an export and a storage protein

    Minor

    The paper identifies ferroportin as involved in Fe export, but later in the same paragraph groups it with proteins involved in Fe storage.

  • Tf and Ft are each presented as the principal intracellular Fe store

    Minor

    The paper calls Tf the principal protein storing Fe inside cells, but later says Fe in tissues is mainly bound to Ft, including inside macrophages and epithelial cells.

3 of 3

Cites

Flagged first, then by citations

1 of the 99 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. 1989, Biochemical Society Transactions, 17, 1118
  2. 1986, Clinical Physiology and Biochemistry, 4, 50

Cited by

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Related

Authors
Leon-Sicairos, N., Reyes-Cortes, R., Guadrón-Llanos, A. M., Madueña-Molina, J., Leon-Sicairos, C., & Canizalez-Román, A.
Affiliations
  • Unidad de Investigación de la Facultad de Medicina, Universidad Autónoma de Sinaloa, Cedros y Sauces, S/N Fracc. Fresnos, 80246 Culiacán, SIN, Mexico
  • Universidad Autónoma de Sinaloa (MX)
  • Doctorado en Biotecnología, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Sinaloa, Avenida de las Américas y Josefa Ortiz (Ciudad Universitaria), 80030 Culiacán, SIN, Mexico
ORCID
Madueña-Molina, Jesús
Venue
BioMed Research International
Publisher
Wiley
Published
2015
Volume
2015
Pages
1-17
ISSN
  • 1110-7243 (ISSN-L)
  • 2314-6133
  • 2314-6141
DOI
10.1155/2015/476534
PMC
PMC4450229
OpenAlex
W1525659589
Semantic Scholar
7e1e06e2124cc9089ea4a7c17d38f6cffc61b743
Cited by
51
References
99
Citations by year
2026: 5 · 2025: 1 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 1
FWCI
0.65
Type
journal article
Language
en
Open access
Licence
Locations
  • BioMed Research International (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Consejo Nacional de Ciencia y Tecnología (CB-2014-236546, PROFAPI-UAS (2014))
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Immunology and Microbiology › Microbiology › Microbial infections and disease research
Keywords
intracellular pathogens, iron acquisition, host-pathogen interaction, macrophages, phagocytosis, iron starvation, bacterial replication, host defense against infection
MeSH terms
Bacteria, Cytoplasm, Humans, Iron, Lysosomes, Macrophages, Phagocytosis, Host-Pathogen Interactions, Cellular Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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