Nutritional Immunity and Metallomic Signatures: Metal Competition at the Host–Pathogen Interface Original paper

What was reviewed?

This comprehensive review by Murdoch and Skaar provides a detailed synthesis of current knowledge on nutritional immunity and metallomic signatures—the dynamic competition for trace metals at the host–pathogen interface. The review explores how vertebrate hosts restrict metal availability to limit bacterial proliferation, while pathogens have evolved diverse acquisition and detoxification strategies to overcome these host defenses. The authors examine the molecular mechanisms underlying metal sequestration and trafficking by both host and pathogens, the tissue- and cell-specific roles of individual metals in infection, and the emerging concept that both metal starvation and intoxication are critical aspects of host defense. Particular attention is given to the molecular machinery involved in metal homeostasis, including siderophores, metallochaperones, metal transporters, and regulatory proteins. The review also highlights recent therapeutic advances that exploit bacterial metal acquisition pathways, such as siderophore–antibiotic conjugates, and discusses the translational potential of nutritional immunity research.

Who was reviewed?

The review synthesizes data from a broad range of studies encompassing both vertebrate hosts (primarily mammals, including humans and animal models) and bacterial pathogens (notably Gram-positive and Gram-negative species such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Mycobacterium tuberculosis, and Neisseria spp.). It also draws on microbiome-focused research, considering commensal and opportunistic bacteria within the gut. It addresses the impact of dietary metal availability and host genetic factors on infection risk and microbiome composition. The review encompasses both in vitro and in vivo studies, as well as translational research on therapeutic interventions targeting metal homeostasis.

Most important findings

This review highlights the pivotal role of trace metal regulation at the host–microbe interface, emphasizing how host-imposed metal sequestration, termed nutritional immunity, restricts microbial access to essential elements like iron, zinc, nickel, and manganese. In response, pathogens evolve countermeasures including siderophore production, high-affinity metal transporters, and metallochaperones to overcome these barriers. The host may also weaponize metals such as copper and zinc to exert antimicrobial pressure.

These dynamic interactions significantly influence the composition of the gut microbiome and infection susceptibility, modulated by dietary metal intake and host genetic polymorphisms. Importantly, the review outlines therapeutic innovations targeting bacterial metal acquisition systems, including siderophore-antibiotic conjugates and host-metal modulating strategies. Finally, the concept of microbial metallomics—taxon-specific metal acquisition and detoxification pathways—emerges as a powerful tool for diagnostics and precision antimicrobial targeting. The review underscores several crucial findings relevant to microbiome signatures, metallomic signatures, microbial metallomics, and clinical translation:

Key Concept	Description
Host Metal Sequestration	Vertebrate hosts utilize proteins like transferrin, lactoferrin, calprotectin, S100 proteins, metallothioneins, and haptoglobin to restrict microbial access to metals in tissues, blood, and mucosa—a process termed nutritional immunity.
Bacterial Adaptation	Pathogens counteract metal sequestration by upregulating siderophores (e.g., staphyloferrin, yersiniabactin), transporters (ZnuABC, FeoB), and metallochaperones (ZigA, YeiR); some exploit host proteins for metal “piracy.”
Metal Intoxication	Host phagocytes may deliver toxic levels of metals (e.g., Cu, Zn) into pathogen-containing compartments to promote oxidative damage and microbial death.
Microbiome and Diet	Variations in dietary metals and host genetics affecting metal metabolism alter microbiome structure and pathogen susceptibility; excess Fe/Zn and nickel (Ni) may favor pathogen overgrowth, while deficiencies impair immune defense.
Therapeutic Advances	Novel antimicrobials like cefiderocol hijack bacterial metal uptake systems; strategies targeting metal acquisition pathways or host metal-binding proteins hold promise for future infection control.
Metallomic Signatures	Pathogen-specific metal-handling systems (e.g., S. aureus Isd system, Yersinia yersiniabactin, Acinetobacter ZnuD) may serve as diagnostic biomarkers or antimicrobial targets within a precision medicine framework.

Key implications

For clinical practice, this review highlights the importance of considering metallomic signatures and metal homeostasis as determinants of infection risk, pathogen virulence, and microbiome stability. Metal acquisition and detoxification systems represent promising targets for next-generation antimicrobials, vaccines, and other microbiome-targeted interventions (MBTIs). Additionally, dietary supplementation or restriction of trace metals should be approached cautiously, as it can influence both beneficial microbiota and pathogen expansion. Recognizing microbial metal-handling signatures may aid in predicting infection risk, guiding therapeutic choices, or developing microbiome or metallome-based diagnostics. The integration of nutritional immunity concepts into clinical microbiology will be critical for advancing precision medicine approaches in infectious disease and microbiome management.

Citation

Murdoch CC, Skaar EP. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface. Nat Rev Microbiol. 2022;20(11):657-670. doi:10.1038/s41579-022-00745-6