Hepcidin and iron‐mediated resistance to malaria

The survival of higher organisms requires constant vigilance against encroachment by potentially pathogenic microorganisms. Every portal of entry, and every potential niche, must be defended simultaneously against a wide spectrum of invaders. Each of these invaders – whether symbiotic or potentially pathogenic – has adopted their own cunning strategy to avoid detection and elimination, and to hijack the host's nutritional resources and metabolic apparatus to multiply and spread. In response to these threats humans have evolved a bewildering array of innate and adaptive defenses of which our knowledge is still only in its infancy. Among the innate defenses are mechanisms designed to withhold nutritional resources from the invaders and, of all the nutrients, iron is by far the most critical. It lies at the epicenter of most host‐pathogen battles for resource control; it is the equivalent of crude oil in global geopolitics.But 32% of the earth's crust is composed of iron (and 88% of its core) making it the most abundant element on the planet, so why should it be the subject of such blatant avarice? And what is the evidence that it is the focus of a fierce arms race between host and pathogen?The avarice is generally explained by the very low solubility of iron compounds in their usual oxidized ferric state and by the usefulness of iron's redox potentials, which make it a suitable co‐factor for numerous enzymes and pathways.The evidence for its centrality in host‐pathogen competition comes, inter alia , from the following sources: (i) most bacteria have made a disproportionate genetic investment in processes for iron acquisition; (ii) many of these genes are concentrated in islands of high pathogenicity, are important in defining niche specificity, and …