Overview

Iron is a pivotal nutrient at the host–pathogen interface. Virtually all microbes (with rare exceptions like Borrelia) require iron for processes from DNA synthesis to respiration. ^[1] In human hosts, free iron is vanishingly scarce due to “nutritional immunity,” wherein iron is locked up in hemoproteins or tightly bound by transport proteins.^[2] This metal tug-of-war underpins many infections: pathogens deploy aggressive iron-scavenging systems to overcome host sequestration, while conditions of iron overload (e.g. hemochromatosis or high-dose supplementation) predispose to invasive infections. Clinically, recognizing iron’s role is vital – both iron deficiency and excess can worsen infection outcomes (the “iron curve” of risk).^[3] The take-home for practitioners is that managing iron levels or targeting microbial iron uptake has emerged as a strategy to modulate pathogen virulence without directly killing bacteria, complementing traditional antibiotics in an era of rising resistance.^[4]

Chemical speciation across host niches

Iron speciation in the human body is highly context dependent, governed by pH, oxygen availability, and host proteins that enforce nutritional immunity. In neutral, oxygenated fluids such as blood and saliva, iron occurs predominantly as ferric (Fe³⁺) bound to high-affinity proteins like transferrin or lactoferrin, with virtually no free iron available.^[5] Acidic environments like the stomach transiently solubilize dietary iron, where reductive chemistry favors ferrous (Fe²⁺) forms that are more bioavailable for absorption in the duodenum.^[6] The colon and urinary tract are essentially iron-restricted niches, with precipitation, microbial chelation, or host proteins (e.g., lactoferrin, siderocalin) further limiting availability.^[7] In contrast, abscesses or wound exudates may temporarily present higher iron availability from heme release, although host hemoprotein scavengers actively counteract this. Collectively, these site-specific conditions ensure microbes experience iron starvation across most host environments, necessitating specialized acquisition strategies. ^[8][9]

Body Site	Iron Speciation & Key Ligands
Blood & Saliva	Fe³⁺ bound to transferrin/lactoferrin; free Fe³⁺ insoluble ^[10]
Gastric Fluid	Acidic (pH ~2); Fe²⁺ solubilized from diet, aided by ascorbate^[11]
Duodenum	pH ~6; Fe²⁺ bioavailable via enterocytes; Fe³⁺ precipitates or complexes^{^[12]}
Colon	Iron-poor; Fe precipitates (e.g., Fe-sulfides); microbial chelation ^{^[13]}
Urine	Essentially iron-free; lactoferrin and siderocalin enforce restriction ^[14]
Abscess/Wounds	Heme-iron released from red cells; scavenged by hemopexin and others ^[15][16][17]

Microbial acquisition, regulation, and nutritional immunity

Bacterial pathogens have evolved a broad toolkit to capture iron, tightly regulated by intracellular iron levels. The breadth of this iron-scavenging arsenal is summarized in the Metal toolkit table below.

Component class	Canonical systems and function with one sentinel pathogen example
Fe²⁺importer	Feo transport system – imports ferrous iron under anaerobic or low pH conditions (Yersinia pestis uses Feo for iron uptake in microaerobic infection niches. ^[18]
Fe³⁺-siderophore uptake	Siderophore receptors and ABC importers – e.g. E. coli FepA/FepB–FepD system imports Fe^3+-enterobactin complexes, enabling growth in iron-depleted serum.^[19]
Heme acquisition	Surface and transporter proteins for heme – e.g. S. aureus Isd system captures hemoglobin, IsdB/IsdH extract heme and IsdEF/IsdC–IsdD import it, fueling heme iron to metabolism.^[20]
Regulator (iron-sensing)	Fur family repressor – senses cytosolic Fe and represses iron uptake genes; e.g. E. coli Fur controls >90 iron-regulated genes, balancing acquisition and avoiding iron toxicity.^[21]
Fe–S cluster assembly	Suf/Isc operons – build essential Fe–S cofactors for enzymes (e.g. in TCA cycle). E. coli Suf is induced during iron starvation or oxidative stress to ensure metalloenzyme maturation under adversity.^[22]
Storage proteins	Bacterioferritin & Ferritin – oxidize and store thousands of Fe^3+ ions in a mineral core. M. tuberculosis upregulates bacterioferritin under stress, linking iron storage to persistence and drug resistance phenotypes.^[23]
Heme efflux	HrtAB transporter – exports excess heme to prevent toxicity. S. aureus activates HrtAB via the HssRS sensor in blood, allowing tolerance of hemoglobin-rich environments (protecting from heme-induced oxidative damage.^[24]

Host iron sequestration

The host employs multiple iron-binding proteins to withhold iron from microbes, often crippling bacterial metalloproteins. Collectively, these host factors create an iron desert that impairs microbial growth and enzyme function, as summarized in the following host sequestration map.

Host factor	Microbial consequence for metal-dependent enzymes or growth

Transferrin (blood plasma)

Binds Fe³⁺ in circulation (K_a ~10^36), keeps free iron <10^(-18) M, forcing pathogens to halt Fe-dependent respiration and DNA synthesis unless they hijack transferrin or use .^[25]

Lactoferrin (secretory)

Chelates Fe³⁺ at mucosal surfaces and in neutrophils ; deprives bacteria of iron, inhibiting growth and biofilm formation (e.g. P. aeruginosa exhibits reduced quorum sensing when iron is -bound, limiting its proteases and toxins).^[26]

Ferritin (intracellular)

Sequesters up to ~4500 Fe atoms inside cells; pathogens unable to access ferritin iron must induce host cell lysis or use siderophores that can extract iron from ferritin. , otherwise their Fe–S enzymes and cytochromes remain starved.^[27]

Haptoglobin–Hemoglobin

Haptoglobin binds any free hemoglobin from hemolysis,, preventing bacterial heme uptake; many hemolytic bacteria (e.g., β-hemolytic streptococci) rely on hemoglobin iron, so haptoglobin slows their growth and virulence by denying heme.^[28]

Hemopexin–Heme

Hemopexin irreversibly sequesters free heme released from degraded Hb; this blocks Gram-negatives that use heme receptors (e.g. E. coli ChuA) from accessing iron, crippling their electron transport if no alternative siderophore is available.^[29]

Siderocalin (NGAL)

Lipocalin-2 from neutrophils binds catecholate siderophores like enterobactin.^[30] As a result, enterobactin-dependent bacteria (E. coli, Klebsiella) cannot acquire iron, yielding bacteriostatic effects. Bacteria with modified siderophores (e.g. glycosylated salmochelin) evade this, highlighting an adaptive arms race.^[31]

Hepcidin (liver hormone)

Induced by IL-6 during infection, hepcidin degrades ferroportin, trapping iron in macrophages and lowering serum iron.^[32] This “strategic anemia” starves extracellular pathogens. However, intracellular microbes (e.g. Salmonella in macrophages) may paradoxically benefit from iron-rich macrophages – a complex dynamic still under investigation.

Metallophores and community competition

Secreted metallophores not only mediate host–pathogen interactions but also drive microbial competition. High-affinity siderophores can act as “public goods” or competitive weapons: enterobactin from E. coli may be pirated by other bacteria with the right receptors, as seen in Vibrio anguillarum which imports exogenous enterobactin to broaden its iron supply.^[33] To escape such vulnerabilities, pathogens like Salmonella and uropathogenic E. coli synthesize salmochelin, a glucosylated enterobactin not bound by host siderocalin, enabling growth under inflammatory stress.^[34] Opportunistic pathogens also exploit host molecules: Pseudomonas aeruginosa has receptors for pyochelin and catecholamine–Fe complexes, while S. aureus similarly acquires iron from stress hormone complexes.^[35][36]Siderophores further shape interspecies dynamics by feeding “cheater” microbes, prompting some producers to evolve antimicrobial siderophore–antibiotic conjugates that act as Trojan horse toxins.^[37] Inflammation amplifies these contests, since cues like IL-1β and hypoxia stimulate siderophore secretion, giving pathogens such as Salmonella a competitive bloom advantage in the gut.^[38] Table Metallophores and capture highlights key metal chelates and who wins in their tug-of-war.

Metallophore or ligand complex	Capture system and ecological effect
Enterobactin–Fe³⁺ (catecholate siderophore)	Host capture: Neutrophil Siderocalin (lipocalin-2) binds Fe–enterobactin tightly, blocking bacterial uptake.^[39] Effect: Siderocalin-sensitive bacteria (e.g. commensal E. coli) lose out, limiting their growth during inflammation.
Salmochelin–Fe³⁺ (glycosylated enterobactin)	Bacterial evasion:Salmonella enterica iroA system produces salmochelin (C-glucosylated enterobactin) which is not bound by lipocalin-2.^[40] Effect:Salmonella secures iron even under host attack, outgrowing Enterobactin-dependent rivals in inflamed gut mucosa.
Ferrichrome–Fe³⁺ (fungal siderophore)	Xenosiderophore uptake: Gram-negatives like E. coliexpress FhuA/FhuBCD to import ferrichrome.^[41] Effect: Iron-scavenging “piracy” – bacteria lacking their own siderophore production (or saving energy) can steal iron from fungal sources, gaining a fitness edge in mixed communities (e.g. gut with yeasts).
Hb–Haptoglobin–Fe (heme in host complex)	Pathogen capture:Neisseria meningitidis and H. influenzae use dedicated receptors (HpuAB, Hxu) to extract heme from Hb–haptoglobin and Hb–hemopexin complexes.^[42] Effect: Allows these pathogens to grow on host hemoglobin iron even when free Hb is absent – a competitive advantage in blood and mucosa, though still limited to species with such receptors.
Catecholamines–Fe³⁺ (Epinephrine, etc.)	Bacterial uptake:S. aureus Sst transporter and P. aeruginosa utilize host stress hormones bound to Fe as siderophores. ^[43][44] Effect: During stress or shock, pathogens opportunistically acquire iron via hormone complexes, enhancing virulence in high-adrenaline environments (e.g. trauma, sepsis).
Microcin–siderophore conjugates	Interference competition: Bacteria like E. coli produce antimicrobial peptides linked to siderophores (e.g. Microcin M); competing bacteria uptake these “Trojan horse” complexes via siderophore receptors.^[45] Effect: Kills or inhibits neighboring microbes that share siderophore pathways, eliminating competition while simultaneously acquiring iron.

Pages

^[46]Staphylococcus aureus HrtA Is an ATPase Required for Protection against Heme Toxicity and Prevention of a Transcriptional

^[47] The Battle for Iron between Bacterial Pathogens and Their Vertebrate Hosts.

^[48] Nutritional immunity: the battle for nutrient metals at the host–pathogen interface.

^[49] The iron curve: infection at both ends. Comment on Mottelson et al, page 693.

^[50] Editorial: Role of Iron in Bacterial Pathogenesis.

^[51] The iron hand of uropathogenic Escherichia coli: the role of transition metal control in virulence.

^[52] Iron metabolism at the host pathogen interface: lipocalin 2 and the pathogen-associated iroA gene cluster

^[53] Interplay between enterobactin, myeloperoxidase and lipocalin 2 regulates E. coli survival in the inflamed gut

^[54] Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection

^[55] Staphylococcus aureus Transporters Hts, Sir, and Sst Capture Iron Liberated from Human Transferrin by Staphyloferrin A, Staphyloferrin B, and Catecholamine Stress Hormones, Respectively, and Contribute to Virulence.

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