Nutritional Immunity and Trace Metals in Infection

What the review examined

This foundational review by Caitlin Murdoch and Eric Skaar (Nature Reviews Microbiology, 2022) synthesizes the concept of nutritional immunity: the coordinated host control of nutrient transition metals to defend against infection. The term originally described iron withholding, but the modern framework encompasses iron (Fe), zinc (Zn), manganese (Mn) and copper (Cu), each of which is essential to microbial metabolism yet toxic in excess.

The review frames the host-pathogen interface as a chemical tug-of-war over the metallome. The host exploits two opposing tactics: metal starvation (withholding Fe, Zn and Mn to deny microbial cofactors) and metal intoxication (flooding compartments with Cu and Zn to poison pathogens). It catalogues the host proteins that execute this control and the microbial countermeasures that circumvent it.

Host machinery of metal withholding

For iron, the host keeps circulating Fe bound to transferrin, sequesters intracellular iron via ferritin, and uses the hormone hepcidin to lower dietary uptake and trap iron in macrophages during inflammation. Freed hemoglobin and heme are captured by haptoglobin and hemopexin, while lactoferrin chelates iron at mucosal surfaces. The result is an extracellular environment nearly devoid of free iron.

For zinc and manganese, the dominant effector is calprotectin (the S100A8-S100A9 heterodimer), which makes up roughly half of neutrophil cytosolic protein and is released abundantly at infection sites. Calprotectin binds Mn2+ and Zn2+ with high affinity, and can also engage Fe, Cu and Ni, producing a broad multi-metal starvation signal in exposed microbes. Manganese starvation is especially damaging because it disables manganese-dependent superoxide dismutases, leaving pathogens vulnerable to the neutrophil oxidative burst.

Metal intoxication inside the phagosome

Nutritional immunity is not only about scarcity. Within professional phagocytes, the transporter NRAMP1 (SLC11A1) pumps iron and manganese out of the pathogen-containing phagosome to starve engulfed microbes, while ATP7A-dependent copper import and ZnT-family zinc transport deliberately raise Cu and Zn to toxic concentrations inside the same compartment.

Excess copper drives mismetallation and Fenton-type oxidative damage, and zinc overload disrupts bacterial metalloenzymes and membrane integrity. Macrophages infected with mycobacteria, for example, concentrate zinc and copper against the pathogen. This dual push-pull of starvation and poisoning is a defining feature of the phagosomal battleground.

Pathogen countermeasures

Microbes fight back with dedicated acquisition systems. Bacteria secrete siderophores to scavenge iron and metallophores such as staphylopine and yersinopine to capture zinc, nickel and other metals. High-affinity importers including the zinc systems ZnuABC (Gram-negative) and AdcABC (Gram-positive) let pathogens extract trace metal even under calprotectin pressure.

To survive metal intoxication, pathogens deploy efflux pumps and detoxifying oxidases that expel or neutralize excess copper and zinc. The review emphasizes that the outcome of infection often hinges on whether host sequestration or microbial acquisition prevails, making these systems attractive antimicrobial targets.

Therapeutic implications

Understanding nutritional immunity has opened metal-based therapeutic avenues. Gallium (Ga3+) acts as an iron mimic: it is taken up by siderophore and iron pathways but cannot be reduced, so it jams iron-dependent enzymes, a 'Trojan-horse' strategy in clinical trials for chronic infection. The FDA-approved siderophore-cephalosporin cefiderocol similarly hijacks bacterial iron import to smuggle an antibiotic across the outer membrane.

Other approaches include targeting metal-uptake transporters as vaccine antigens, modulating hepcidin to reshape iron availability, and pairing metal restriction with oxidative or antibiotic stress. These strategies aim to weaponize the host's own metal-control logic against resistant pathogens.

Fit within the metal-microbiome-disease axis

Nutritional immunity is the molecular grammar linking metals, microbes and disease. The same host proteins that starve pathogens also shape resident microbial communities: calprotectin and iron withholding alter which taxa thrive in the inflamed gut, and enteric pathogens such as Salmonella exploit inflammation-driven metal fluxes to outcompete commensals. This ties directly to the metal-microbiome-disease axis, in which metal exposure and metal handling reshape microbial ecology.

By extension, environmental heavy-metal burden does not act on the microbiome in a vacuum. It is layered on top of the host's finely tuned metal-restriction systems. Perturbing metallostasis, whether through toxic-metal exposure or dysregulated nutritional immunity, can shift microbial communities in ways that promote colonization, inflammation and disease, providing a mechanistic bridge between metal exposure, microbiome disruption and clinical outcomes.