In this issue, Liu et al. provide compelling evidence for a novel mechanism by which pathogenic bacteria can acquire iron from mammalian cells.

Iron is an essential nutrient for almost all organisms due to its central role in many enzymatic processes, mitochondrial respiration, and DNA synthesis. Most microbes are highly dependent on a sufficient supply of iron to secure their growth, and they can acquire this essential nutrient by multiple pathways. One of these acquisition strategies is via the release of bacterial siderophores, which capture iron in the environment and are then taken up by microbes.

Mammalian cells also produce a siderophore, which is presumably used for intracellular and transcellular iron shuttling. Liu et al. found that this mammalian siderophore, 2,5-dihydroxybenzoic acid (2,5-DHBA), can be taken up by bacteria and used as a source for iron. Synthesis of 2,5-DHBA was reduced upon bacterial infection, and knock out of this mammalian siderophore resulted in increased resistance of mice to infection with E. coli. Importantly, mammalian immune cells also produce the peptide lipocalin-2 in response to infection, which sequesters both bacterial and mammalian siderophores. Thus, combined down-regulation of 2,5-DHBA and up-regulation of lipocalin-2 restricts iron availability for microbes, resulting in a beneficial infection outcome.

Given the importance of iron for microbial growth and for antimicrobial immune defenses, the struggle for control over iron availability is a central battlefield that may decide the fate of an infection. This study describes a novel pathway by which bacteria steal the nutrient iron from the mammalian host to secure their own growth and pathogenicity. Targeting both mammalian and microbial iron homeostasis is an attractive approach to tackle iron availability for microbes and to treat infections, a strategy first studied in malaria and hepatitis C virus infection with varying outcomes, but not yet in bacterial infections in humans. However, it has to be kept in mind that restricting iron availability for extracellular microbes may favor the growth of pathogens residing within cells and vice versa. Moreover, we need to gain further insights into the role of the mammalian siderophores in orchestrating mammalian iron homeostasis under normal and inflammatory or infectious conditions, and how the pharmacological inhibition of 2,5-DHBA synthesis will impact host immune function, erythropoiesis, and iron-dependent cellular processes.

et al
J. Exp. Med.