The battle for iron between bacterial pathogens and hosts: clinical microbiome implications Original paper

What was reviewed?

This narrative review synthesizes the battle for iron between bacterial pathogens and hosts, focusing on vertebrate nutritional immunity and the microbial countermeasures that enable infection despite iron scarcity. It explains how vertebrates sequester iron intracellularly in ferritin and within heme, bind extracellular iron with high-affinity transferrin, and mop up free hemoglobin and heme via haptoglobin and hemopexin, thereby rendering free iron essentially unavailable to invaders. The article also details how pathogens sense iron limitation through regulators such as Fur and DtxR, and how they respond by deploying iron acquisition systems. The figure on page 2 visualizes this “iron battlefield” in health versus infection, highlighting host ligands, neutrophil lactoferrin release during inflammation, and bacterial receptors for transferrin, lactoferrin, hemoglobin, and hemophores.

Who was reviewed?

The review integrates host factors and representative pathogens across taxa. On the host side, it covers transferrin with an association constant near 10^36 for ferric iron, ferritin, lactoferrin from neutrophil granules, and hemopexin and haptoglobin that capture heme and hemoglobin. On the pathogen side, it describes Neisseria and Pasteurellaceae that express transferrin and lactoferrin receptors, Staphylococcus aureus that uses the Isd heme uptake machinery, Bacillus anthracis that produces the stealth siderophore petrobactin, Salmonella Typhimurium that produces salmochelin to evade siderocalin, and Borrelia burgdorferi which uniquely substitutes manganese to minimize iron dependence. The review also notes that individuals with iron overload, such as in hemochromatosis, are unusually susceptible to pathogens like Vibrio vulnificus, underscoring the clinical relevance of host iron status.

Most important findings

The central insight is that vertebrates practice nutritional immunity by withholding iron, while pathogens have evolved layered, high-affinity systems to overcome this barrier. In health, iron remains intracellular or tightly liganded, and transferrin renders free extracellular iron effectively insoluble; during infection, tissue damage and hemolysis increase the availability of hemoproteins, while inflammation releases lactoferrin, yet bacteria still require dedicated uptake systems to compete. Bacterial strategies fall into three principal categories: siderophore systems with subnanomolar to femtomolar iron-binding affinity that strip iron from transferrin or ferritin, heme acquisition through surface receptors and hemophores followed by cytosolic heme oxygenase or reverse ferrochelatase processing, and direct receptor-mediated removal of iron from transferrin and lactoferrin.

The host counters siderophore piracy with siderocalin (NGAL), which binds catecholate siderophores such as enterobactin and prevents their uptake. Bacteria, in turn, produce stealth siderophores like petrobactin and salmochelin that evade siderocalin binding, restoring iron access and virulence fitness. Human challenge data indicate that expression of both lactoferrin and transferrin receptors confers a selective advantage to Neisseria gonorrhoeae, reinforcing the concept that iron receptors are in vivo fitness determinants. Collectively, these mechanisms provide a coherent framework for linking microbial iron acquisition to virulence and for understanding how host iron status modulates pathogen selection pressures, with implications for microbiome signatures where enterobactin-dependent Enterobacteriaceae may be disadvantaged in high siderocalin states.

Key implications

Clinically, iron availability is a modifiable ecological variable that shapes pathogen success and likely influences community structure in infected niches. Elevated iron exposure, whether iatrogenic or from overload disorders, can reduce the effectiveness of nutritional immunity and favor siderophore-competent pathogens, which argues for extremely judicious iron administration during active infection and careful interpretation of transferrin saturation and ferritin in at-risk patients. Because iron uptake receptors and heme transporters are surface-exposed and induced during infection, they represent tractable vaccine antigens and therapeutic targets. Host effectors such as siderocalin highlight the feasibility of boosting endogenous nutritional immunity, while the emergence of stealth siderophores underscores the need for therapeutics that neutralize both classical and modified siderophores. For microbiome-informed practice, linking disease-associated pathogen blooms to iron handling, lactoferrin dynamics, and siderophore ecology can guide targeted interventions that either limit iron availability or block specific acquisition pathways.

Citation

Skaar EP. The Battle for Iron between Bacterial Pathogens and Their Vertebrate Hosts. PLoS Pathogens. 2010;6(8):e1000949. doi:10.1371/journal.ppat.1000949.