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

The DOI matches its Crossref record; 97 of the 97 references it cites were found in a registry or an index; none of the 83 sources its claims cite is checked for support yet.

Iron in Infection and Immunity

Open access
Cassat, James E., Skaar, Eric P.·2013·Cell Host & Microbe

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.

Overview

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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).

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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.

Verification

Claims the paper makes

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

Show all 66 claims

  • It may state two separate claims as one. 39
  • Probably not a substantial claim. 7
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.”
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Metadata

Authors
Cassat, J. E., & Skaar, E. P.
Affiliations
  • Vanderbilt University Medical Center (US)
  • Vanderbilt University (US)
Corresponding author
Skaar, Eric P.
Venue
Cell Host & Microbe
Publisher
Elsevier BV
Published
2013-05
Volume
13
Issue
5
Pages
509-519
ISSN
1931-3128 (ISSN-L)
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
FWCI
9.11
Type
journal article
Language
en
Open access
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 › Materials Science › Metals and Alloys › 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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