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Cited by 1,252Iron Metabolism and DisordersBacterial Genetics and BiotechnologyIron and Steelmaking Processes

Iron in infection and immunity

Open access
Cassat, James E., Skaar, Eric P.·2013·Cell Host & Microbe
DOI 10.1016/j.chom.2013.04.010PMC PMC3676888
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Abstract

Iron is an essential nutrient for both humans and pathogenic microbes. Because of its ability to exist in one of two oxidation states, iron is an ideal redox catalyst for diverse cellular processes including respiration and DNA replication. However, the redox potential of iron also contributes to its toxicity; thus, iron concentration and distribution must be carefully controlled. Given the absolute requirement for iron by virtually all human pathogens, an important facet of the innate immune system is to limit iron availability to invading microbes in a process termed nutritional immunity. Successful human pathogens must therefore possess mechanisms to circumvent nutritional immunity in order to cause disease. In this review, we discuss regulation of iron metabolism in the setting of infection and delineate strategies used by human pathogens to overcome iron-withholding defenses.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that because nearly all human pathogens require iron, withholding iron from microbes (nutritional immunity) is a central innate immune strategy, and successful pathogens must evolve countermeasures to cause disease. It surveys host iron homeostasis, microbial acquisition and detoxification strategies across bacteria, fungi, and parasites, and therapeutic approaches that target pathogen iron metabolism.

Key findings

  • Human iron metabolism is highly conserving: adults hold roughly 4–5 g of total body iron while losing only about 0.5–1 mg daily, and healthy transferrin is typically under 50% iron-saturated, leaving little free extracellular iron for microbes.
  • Infection triggers hypoferremia, orchestrated largely by hepcidin (which drives ferroportin internalization and degradation) plus hepcidin-independent cytokine effects; local sequestration adds lactoferrin, Nramp1, and siderocalin/lipocalin-2.
  • Pathogens use five main acquisition routes — manganese substitution (e.g., *Borrelia burgdorferi*), siderophores (binding constants exceeding 10^50 versus transferrin's ~10^36), heme uptake systems, transferrin/lactoferrin receptors, and ferric/ferrous transporters — and some produce "stealth siderophores" that evade siderocalin.
  • Iron overload states such as hereditary hemochromatosis and thalassemia raise infection susceptibility (e.g., *Yersinia* spp., *Listeria monocytogenes*, *Vibrio vulnificus*), though hemochromatosis monocytes are reportedly less permissive to *M. tuberculosis*.
  • Therapeutic avenues include siderophore-biosynthesis inhibitors (e.g., p-aminosalicylic acid), sideromycin conjugates (albomycin, MC-1), and vaccines against iron-acquisition proteins (IsdA/IsdB, uropathogenic *E. coli* iron receptors, hookworm Na-APR-1).

Methods

Narrative review; no primary data or systematic search strategy is described. Evidence is synthesized from cited primary literature spanning human iron physiology, animal and in vitro infection models, and clinical observations (e.g., the 1940s canine *S. aureus* hypoferremia experiments, mouse models, and human vaccine trial outcomes). Sections are organized by host homeostasis, bacterial (extracellular and intracellular), fungal, and parasitic iron handling, then therapeutics.

Limitations

The paper states several open questions: which redundant microbial iron-acquisition components matter most for pathogenesis, which are best suited to vaccine construction, whether the hepcidin axis can be therapeutically manipulated for tolerance, and whether mammalian siderophores function in nutritional immunity. It notes that the terminated *S. aureus* IsdB-containing human vaccine trial shows animal protection may not predict human efficacy. Evident from the text: as a review, it offers no new experimental data, and several claims rest on single or dated sources (e.g., textbook citations for epidemiologic figures such as hookworm and malaria burden).

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

Integrity signals

Registry

Crossref · 10.1016/j.chom.2013.04.010

Cites

97 of 97 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 83 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Acquisition of heme by the Isd system is critical for Staphylococcus aureus pathogenesis.

    “Acquisition of heme by the Isd system is critical for S. aureus pathogenesis (Cassat and Skaar, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cassat and Skaar, 2012 source

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  • Interpretationreasoning

    Regulation of iron distribution acts as an innate immune mechanism against invading pathogens.

    “In addition to mitigating toxicity associated with hypo- or hyperferremia, regulation of iron distribution serves as an innate immune mechanism against invading pathogens.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Patients with iron overload from hemochromatosis and thalassemia are more susceptible to infection with Yersinia spp., Listeria monocytogenes, and Vibrio vulnificus.

    “Patients with iron overload from hemochromatosis and thalassemia are more susceptible to infection with Yersinia spp., Listeria monocytogenes, and Vibrio vulnificus, among others (Long et al., 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Long et al., 2003

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  • Premisecitation

    Nramp1 has been proposed to reduce iron content in early endosomes, thereby limiting iron availability to intracellular pathogens in that compartment.

    “Nramp1 (natural resistance associated macrophage protein-1) is a divalent metal ion transporter that has been proposed to reduce iron content in early endosomes, thereby limiting availability to intracellular pathogens in this compartment (Jabado et al., 2000; Vidal et al., 1995).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jabado et al., 2000 source

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    • cites Vidal et al., 1995 source

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  • Premisereasoning

    Hemolytic pathogens that liberate hemoglobin must compete with haptoglobin and hemopexin, host glycoproteins that scavenge hemoglobin and heme.

    “However, hemolytic pathogens must subsequently compete with haptoglobin and hemopexin, host glycoproteins that scavenge liberated hemoglobin and heme, respectively (Figure 1D).”
    Quote in the paperSubstantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisereasoning

    Iron can cycle between ferrous and ferric oxidation states, which allows it to act as a redox catalyst in cellular processes.

    “Because of its ability to exist in one of two oxidation states, iron is an ideal redox catalyst for diverse cellular processes including respiration and DNA replication.”
    • Also stated in: § Ia. Human iron homeostasis · plain
      “The biologic utility of iron resides in its ability to cycle between two oxidation states: ferrous (Fe2+) or ferric (Fe3+). Iron can thus serve as a redox catalyst, accepting or donating electrons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Iron is an essential nutrient for humans and for pathogenic microbes.

    “Iron is an essential nutrient for both humans and pathogenic microbes.”
    • Also stated in: § Ia. Human iron homeostasis · plain
      “Iron is an essential nutrient for humans, with critical functions in many cellular processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Vibrio vulnificus, Staphylococcus aureus, and Yersinia enterocolitica can utilize desferrioxamine B as an iron source.

    “For example, V. vulnificus, S. aureus, and Y. enterocolitica, among others, can utilize desferrioxamine B as an iron source.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kim et al., 2007 source

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    Premisecitation

    Neisseria meningitidis expresses both transferrin and lactoferrin uptake systems and preferentially utilizes human transferrin.

    “Neisseria meningitidis expresses both transferrin and lactoferrin uptake systems. Consistent with its role as an obligate human pathogen, N. meningitidis preferentially utilizes human transferrin (Schryvers and Morris, 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schryvers and Morris, 1988 source

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  • May combine two claims.

    Premisecitation

    Unlike transferrin, lactoferrin maintains iron-binding capacity at low pH and may therefore be a more effective scavenger in acidotic infectious foci.

    “Moreover, unlike transferrin, lactoferrin maintains iron-binding capacity at low pH and therefore may be a more effective scavenger in acidotic infectious foci (Baker and Baker, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baker and Baker, 2012 source

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    Premisecitation

    Neutrophil secondary granules contain lactoferrin, which is released at infectious sites in response to cytokines.

    “Additionally, the specific (“secondary”) granules of neutrophils contain lactoferrin, which is released at infectious sites in response to cytokines (Masson et al., 1969).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Masson et al., 1969 source

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  • May combine two claims.

    Premisenone given

    In healthy people, nearly all iron released into plasma is bound to transferrin, which limits free radical production and facilitates transport to target cells.

    “In healthy individuals, nearly all iron released into plasma is bound to transferrin, limiting iron-catalyzed free radical production and facilitating transport to target cells.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Hepcidin was initially characterized as an antimicrobial peptide in human urine and blood ultrafiltrate.

    “In fact, hepcidin was initially characterized as an antimicrobial peptide in human urine and blood ultrafiltrate (Krause et al., 2000; Park et al., 2001).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Krause et al., 2000 source

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    • cites Park et al., 2001 source

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  • May combine two claims.

    Premisenone given

    Most iron in humans is sequestered intracellularly within hemoglobin inside erythrocytes, making it poorly accessible to pathogenic microorganisms.

    “First, the majority of iron in humans is sequestered intracellularly, complexed within hemoglobin inside erythrocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Increases in total body iron stores trigger hepcidin production, which induces internalization and degradation of ferroportin.

    “Increases in total body iron stores trigger the production of hepcidin, which subsequently induces the internalization and degradation of ferroportin (Nemeth et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nemeth et al., 2004 source

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  • May combine two claims.

    Premisenone given

    Most iron in humans is contained within hemoglobin, and many pathogens have developed mechanisms to liberate hemoglobin from erythrocytes and use heme as a nutrient.

    “As most iron in humans is contained within hemoglobin, many pathogens have developed mechanisms to liberate hemoglobin from erythrocytes and utilize heme as a nutrient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hepcidin release from the liver is stimulated by pro-inflammatory cytokines, TLR activation, and induction of the endoplasmic reticulum unfolded protein response.

    “Hepcidin release from the liver is stimulated by pro-inflammatory cytokines, TLR activation, and induction of the endoplasmic reticulum unfolded protein response (Figure 2A) (Drakesmith and Prentice, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Drakesmith and Prentice, 2012 source

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    Premisecitation

    Hepcidin is produced in the liver and post-translationally regulates ferroportin, controlling entry of iron into plasma after enterocyte absorption.

    “Hepcidin, a peptide hormone produced in the liver, post-translationally regulates ferroportin and thus controls entry of iron into the plasma after enterocyte absorption.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nemeth et al., 2004 source

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    Premisecitation

    Siderophores are small ferric iron chelators produced by many Gram-positive and Gram-negative human pathogens, with iron-binding association constants that can exceed 10^50.

    “Produced by a wide range of Gram-positive and Gram-negative human pathogens, siderophores are small ferric iron chelators capable of binding iron with association constants that can exceed 1050 (Bullen JJ, 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bullen JJ, 1999

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  • May combine two claims.

    Premisenone given

    Pseudomonas aeruginosa expresses both a direct heme uptake system and a hemophore-mediated heme acquisition system.

    “P. aeruginosa expresses both a direct uptake system and hemophore-mediated system for heme acquisition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    During infection, plasma iron levels drop; Cartwright et al. observed this hypoferremia in canines after intramuscular inoculation with Staphylococcus aureus.

    “The hypoferremia of infection was documented in seminal studies by2 Cartwright et al. in the 1940s, who noted a precipitous drop in plasma iron levels upon intramuscular inoculation of canines with Staphylococcus aureus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cartwright et al., 1946 source

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    Premisecitation

    The hypoferremic response to infection is also mediated by hepcidin-independent mechanisms, with cytokines such as interferon-gamma, tumor necrosis factor-alpha, IL-1, and IL-6 modulating iron metabolism.

    “The hypoferremic response to infection is also mediated by hepcidin-independent mechanisms. Cytokines such as interferon-gamma, tumor necrosis factor-alpha, IL-1, and IL-6 modulate iron metabolism to further strengthen iron-withholding defenses (Figure 2B – C) (Nairz et al., 2010; Weiss, 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nairz et al., 2010 source

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    • cites Weiss, 2005 source

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  • May combine two claims.

    Premisenone given

    Siderophores are synthesized under low iron conditions and secreted, where they bind ferric iron and facilitate its use by microbial cells.

    “They are synthesized under conditions of low iron availability and secreted into the extracellular environment, where they bind ferric iron and facilitate its use by microbial cells (Figure 3A–3B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Borrelia burgdorferi uses manganese instead of iron in metalloenzymes, eliminating its need for iron acquisition systems.

    “One mechanism, used by Borrelia burgdorferi, is to utilize manganese instead of iron in metalloenzymes, thereby eliminating the need for iron acquisition systems (Posey and Gherardini, 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Posey and Gherardini, 2000 source

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  • May combine two claims.

    Premisenone given

    Extracellular iron is bound with high affinity by transferrin, which in healthy individuals is typically less than 50% saturated with iron.

    “Extracellular iron is bound with high affinity by transferrin, which in healthy individuals is typically less than 50% saturated with iron.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Lactoferrin binds free iron with high affinity, and mucosal secretions contain high concentrations of it, providing a constitutive mechanism for iron limitation at mucosal surfaces.

    “Lactoferrin is a host glycoprotein that, like transferrin, binds free iron with high affinity. Mucosal secretions contain high concentrations of lactoferrin, comprising a constitutive mechanism for iron limitation at mucosal surfaces.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Siderocalin is expressed during the acute phase response to infection and sequesters siderophores.

    “Siderocalin, also known as lipocalin-2 (Lcn2) or neutrophil gelatinase-associated lipocalin, is expressed during the acute phase response to infection and sequesters siderophores (Figure 2D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mycobacterium tuberculosis acquires iron either from transferrin as it cycles through the endocytic pathway or from cytoplasmic iron stores.

    “Radiolabeling studies demonstrated that Mtb acquires iron either from transferrin as it cycles through the endocytic pathway, or from cytoplasmic iron stores (Olakanmi et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Olakanmi et al., 2002 source

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    Interpretationcitation

    Polymorphisms in Nramp1 correlate with enhanced human susceptibility to Mycobacterium tuberculosis, suggesting that intraphagosomal iron limitation might be an important innate immune defense.

    “Polymorphisms in Nramp1 have been found to correlate with enhanced human susceptibility to Mycobacterium tuberculosis (Mtb), suggesting that intraphagosomal iron limitation might be an important innate immune defense (van Crevel et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites van Crevel et al., 2009 source

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    Premisecitation

    Pathogenic mycobacteria express siderophores called mycobactins, and disruption of mycobactin synthesis impairs growth within macrophages.

    “Similar to predominantly extracellular pathogens, pathogenic mycobacteria express siderophores known as mycobactins, the biosynthesis of which has been elegantly investigated using lipidomics profiling (Madigan et al., 2012). Disruption of mycobactin synthesis impairs growth within macrophages, suggesting that siderophore production is an important iron acquisition strategy for Mtb (De Voss et al.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites De Voss et al., 2000 source

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  • May combine two claims.

    Premisenone given

    Siderocalin binds the Escherichia coli siderophore enterochelin and inhibits its growth.

    “Siderocalin was initially characterized by its ability to bind the E. coli siderophore enterochelin, inhibiting its growth.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    More than 700 million people worldwide are infected by human hookworms.

    “Human hookworms infect greater than 700 million people worldwide and are a leading cause of iron deficiency anemia in the developing world (Long et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Long et al., 2003

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    Premisecitation

    When erythrocytes rupture, hemozoin enters the circulation and is taken up by phagocytes, where it strongly modulates immune responses.

    “After erythrocyte rupture, hemozoin is released into the circulation and ingested by phagocytes, where it has profound immunomodulatory effects (Hanscheid et al., 2007; Shio et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hanscheid et al., 2007 source

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    • cites Shio et al., 2010 source

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

    Premisecitation

    Human hookworms are a major cause of iron deficiency anemia in developing countries.

    “Human hookworms infect greater than 700 million people worldwide and are a leading cause of iron deficiency anemia in the developing world (Long et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Long et al., 2003

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  • May combine two claims.

    Premisereasoning

    P. falciparum uses host hemoglobin as a nutrient and has developed a specific way to avoid iron toxicity.

    “Similar to human hookworms, P. falciparum also uses host hemoglobin as a nutrient source, and has evolved a distinct mechanism for protecting against iron toxicity.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Malaria is caused by one of five species of Plasmodium, with P. falciparum being the most virulent.
    • Rests on an assumption: Hemoglobin is ingested by intra-erythrocytic Plasmodia, transported to a food vacuole, and degraded to nutrient amino acids by a proteolytic cascade.

  • May combine two claims.

    Interpretationcitation

    Although hereditary hemochromatosis generally enhances susceptibility to infectious disease, certain subtypes may confer a selective advantage against intracellular pathogens.

    “Therefore, although hereditary hemochromatosis generally enhances susceptibility to infectious disease, certain subtypes may confer a selective advantage against intracellular pathogens.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Olakanmi et al., 2002 source

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  • May combine two claims.

    Premisecitation

    Lcn2 is crucial for controlling parasitemia by suppressing reticulocytosis, improving macrophage function, and modulating adaptive immunity.

    “Lcn2 plays a critical role in control of parasitemia through suppression of reticulocytosis, enhancement of macrophage function, and modulation of adaptive immune responses (Zhao et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhao et al., 2012 source

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    • Rests on an assumption: Lcn2 is abundantly produced during malaria.

  • May combine two claims.

    Premisecitation

    Disruption of Mycobacterium tuberculosis ferritin biosynthesis limits resistance to oxidative stress, enhances susceptibility to antibiotics, and decreases bacterial survival in a chronic infection model.

    “For example, disruption of Mtb ferritin biosynthesis limits resistance to oxidative stress, enhances susceptibility to antibiotics, and decreases bacterial survival in a chronic infection model (Pandey and Rodriguez, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pandey and Rodriguez, 2012 source

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    Premisecitation

    HssRS senses heme exposure, increasing expression of hrtAB, which alleviates heme toxicity.

    “HssRS senses heme exposure, increasing expression of hrtAB, which results in alleviation of heme toxicity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stauff et al., 2007 source

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    Premisecitation

    Patients with hereditary hemochromatosis have reduced intracellular iron levels, and monocytes derived from them are less permissive to Mycobacterium tuberculosis replication.

    “Interestingly, patients with hereditary hemochromatosis have reduced intracellular iron levels, and thus monocytes derived from such individuals are less permissive to Mtb replication (Olakanmi et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Olakanmi et al., 2002 source

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    Premisecitation

    Up to 2 million people die from malaria each year.

    “Up to two-thirds of the world’s population are exposed to malaria annually, of which over 240 million will contract the disease and up to 2 million will die (Long et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Long et al., 2003

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

    Premisenone given

    Antimicrobial compounds and vaccines that target pathogen iron homeostasis are under development.

    “Both antimicrobial compounds and vaccines targeting pathogen iron homeostasis are currently being developed.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The vast majority of human pathogens require iron to sustain growth and colonize humans.

  • May combine two claims.

    Premisecitation

    Ferroportin rapidly localizes to Mycobacterium tuberculosis-infected phagolysosomes, resulting in iron efflux from that compartment.

    “Additionally, ferroportin rapidly localizes to Mtb-infected phagolysosomes, resulting in iron efflux from this cellular compartment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Van Zandt et al., 2008 source

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

    Premisecitation

    More than 240 million people contract malaria annually.

    “Up to two-thirds of the world’s population are exposed to malaria annually, of which over 240 million will contract the disease and up to 2 million will die (Long et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Long et al., 2003

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  • May combine two claims.

    Premisenone given

    Pathogenic fungi must obtain iron from host tissues and regulate iron homeostasis to avoid toxicity.

    “Pathogenic fungi, like bacterial pathogens, must obtain iron from host tissues and regulate iron homeostasis to avoid toxicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Albomycin protects mice against systemic infection with S. pneumoniae and Y. enterocolitica.

    “Albomycin, a sideromycin produced by Streptomyces spp., protects mice from S. pneumoniae and Y. enterocolitica systemic infection (Pramanik et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pramanik et al., 2007 source

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  • May combine two claims.

    Premisecitation

    These siderophores support germination and oxidative stress resistance by ensuring proper intracellular iron distribution.

    “By maintaining proper intracellular iron distribution, these compounds promote germination and resistance to oxidative stress, and are required for full virulence in a mouse model of invasive infection (Schrettl et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schrettl et al., 2007 source

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

    Premisecitation

    Up to two-thirds of the global population is exposed to malaria each year.

    “Up to two-thirds of the world’s population are exposed to malaria annually, of which over 240 million will contract the disease and up to 2 million will die (Long et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Long et al., 2003

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  • May combine two claims.

    Premisecitation

    The synthetic siderophore-conjugated beta-lactam MC-1 is effective against P. aeruginosa in vitro and in vivo.

    “Similarly, the synthetic siderophore-conjugated beta-lactam MC-1, is active against P. aeruginosa both in vitro and in vivo (McPherson et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McPherson et al., 2012 source

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  • May combine two claims.

    Interpretationreasoning

    The Plasmodium life cycle has an intra-erythrocytic stage, which provides a unique chance to access the host's largest iron reservoir.

    “The Plasmodium lifecycle includes an intra-erythrocytic stage, creating a unique opportunity to manipulate the richest reservoir of iron in the host.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Malaria is caused by one of five species of Plasmodium, with P. falciparum being the most virulent.

  • May combine two claims.

    Premisecitation

    Aspergillus fumigatus produces two intracellular siderophores: ferricrocin in hyphae and hydroxyferricrocin in conidia.

    “A. fumigatus, an important cause of invasive disease in immunocompromised patients, produces two intracellular siderophores: hyphal ferricrocin and conidial hydroxyferricrocin (Schrettl and Haas, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schrettl and Haas, 2011 source

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46 of 46

  • The paper relies on this without support.

    The vast majority of human pathogens require iron to sustain growth and colonize humans.

    “The vast majority of human pathogens require iron to sustain growth and colonize humans.”

  • The paper relies on this without support.

    Hookworms feed on human blood, using a hemolysin to lyse erythrocytes and anticoagulants to resist clotting.

    “Hookworms feed on human blood, using a hemolysin to lyse erythrocytes and anticoagulants to resist clotting.”

  • The paper relies on this without support.

    Malaria is caused by one of five species of Plasmodium, with P. falciparum being the most virulent.

    “Malaria is caused by one of five species of Plasmodium, with P. falciparum being the most virulent.”

  • The paper relies on this without support.

    Hemoglobin is ingested by intra-erythrocytic Plasmodia, transported to a food vacuole, and degraded to nutrient amino acids by a proteolytic cascade.

    “Hemoglobin is ingested by intra-erythrocytic Plasmodia, transported to a specialized organelle known as the food vacuole, and degraded to nutrient amino acids by a proteolytic cascade.”

  • The paper relies on this without support.

    Digestion of hemoglobin releases heme, which is toxic at elevated concentrations.

    “However, digestion of hemoglobin also releases heme, which is toxic at elevated concentrations.”

  • The paper relies on this without support.

    Plasmodia sequester heme into hemozoin, which accumulates in organs of infected individuals.

    “To limit toxicity, Plasmodia sequester heme into a pigment known as hemozoin, which accumulates in the organs of infected individuals.”

  • The paper relies on this without support.

    Non-Typhoid Salmonella (NTS) bacteremia is a common and often fatal complication of malaria.

    “Non-Typhoid Salmonella (NTS) bacteremia is a common and often fatal complication of malaria.”

  • The paper relies on this without support.

    Hemolysis during malaria induces the expression of HO-1, which protects host cells by detoxifying heme.

    “Hemolysis during malaria induces the expression of HO-1, which protects host cells by detoxifying heme.”

  • The paper relies on this without support.

    Lcn2 is abundantly produced during malaria.

    “The siderophore-sequestering molecule Lcn2 is abundantly produced during malaria.”

  • The paper relies on this without support.

    Siderophore conjugation decreases the minimum inhibitory concentration of several antibiotics, including beta-lactams, vancomycin, and fluoroquinolones.

    “Siderophore conjugation decreases the minimum inhibitory concentration of several antibiotics, including beta-lactams, vancomycin, and fluoroquinolones.”

  • The paper relies on this without support.

    The Na-APR-1 protease from human hookworm, Necator americanus, is essential for enzymatic activity to support blood feeding.

    “The Na-APR-1 protease from human hookworm, Necator americanus, is essential for enzymatic activity to support blood feeding.”
11 of 11

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?

  • Elevated concentrations of hepcidin increase iron sequestration by macrophages and decrease duodenal iron absorption during inflammatory reactions, thus reducing plasma iron levels.

    “Elevated concentrations of hepcidin increase iron sequestration by macrophages and decrease duodenal iron absorption during inflammatory reactions and thus reduces plasma iron levels (Cassat and Skaar, 2013; Noble, 2013).”

    From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Cassat and Skaar, 2013

  • Iron can directly promote microbial growth.

    “In addition, iron can directly promote microbial growth (Cassat and Skaar, 2013), Zimmermann et al. (2010) reported an increase in enteric pathogens with iron supplementation.”

    From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Cassat and Skaar, 2013

  • Control over iron homeostasis is decisive in host-pathogen interaction.

    “The control over iron homeostasis is decisive in host–pathogen interaction (Schaible and Kaufmann, 2004; Nairz et al., 2010; Cassat and Skaar, 2013).”

    From Iron at the interface of immunity and infection (2014) · cites this paper as Cassat and Skaar, 2013

  • Many microbes are highly dependent on a sufficient supply of iron and take up this metal by multiple and divergent pathways or steal it from iron deposition sites of the host.

    “Many microbes are highly dependent on a sufficient supply of iron and take up this metal by multiple and divergent pathways or steel it from iron deposition sites of the host (Winkelmann, 2002; Cassat and Skaar, 2013; Frawley et al., 2013).”

    From Iron at the interface of immunity and infection (2014) · cites this paper as Cassat and Skaar, 2013

  • Because microbes multiply rapidly and undergo clonal selection, they can escape growth-limiting conditions such as host iron sequestration.

    “Rapid microbial multiplication and clonal selection allow microorganisms to evade conditions that restrict their growth, including iron sequestration by their hosts79.”

    From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [79]

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Authors
Cassat, J. E., & Skaar, E. P.
Affiliations
  • Vanderbilt University Medical Center (US)
  • Vanderbilt University (US)
Corresponding author
Skaar, Eric P.
ORCID
Venue
Cell Host & Microbe
Publisher
Elsevier BV
Published
2013-05
Volume
13
Issue
5
Pages
509-519
ISSN
1931-3128 (ISSN-L)
DOI
10.1016/j.chom.2013.04.010
PMC
PMC3676888
OpenAlex
W2044678473
Cited by
1,214
References
97
Citations by year
2026: 62 · 2025: 90 · 2024: 91 · 2023: 106 · 2022: 145 · 2021: 150 · 2020: 112 · 2019: 108 · 2018: 84 · 2017: 83 · 2016: 71 · 2015: 62 · 2014: 39 · 2013: 7 · 2012: 1
FWCI
9.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Host & Microbe (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Allergy and Infectious Diseases (L40 AI096516, R01AI069233, R01AI073843, R01AI101171)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Physical Sciences › Engineering › Mechanical Engineering › Iron and Steelmaking Processes
Keywords
iron metabolism, nutritional immunity, iron acquisition, iron regulation, innate immunity, host-pathogen interaction, iron redox chemistry, iron toxicity
MeSH terms
Animals, Bacteria, Communicable Diseases, Fungi, Homeostasis, Humans, Immunity, Innate, Iron, Models, Biological, Parasites

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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 2026-10-05.

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