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Metal Availability and Immune Function During Infection
Clinical Overview
This narrative review synthesizes how availability of zinc, iron (including heme-bound iron), manganese, and copper shapes innate immune function during infection across bacterial, fungal, and protozoan pathogens. The authors integrate data from murine models, human cells, and in vitro systems to show that the same metal redistribution that starves or intoxicates microbes also rewires neutrophil and macrophage behavior via effects on phagocytosis, respiratory burst, NET formation, antigen presentation, and cytokine signaling. Key qualitative effects include zinc-dependent modulation of NF-κB, MAPK and NLRP3 inflammasome activity; hepcidin-driven intracellular iron loading that blunts iNOS and IFN-γ–inducible pathways; manganese enhancement of cGAS–STING antiviral sensing; and copper-dependent tuning of neutrophil counts and oxidative burst. Metal-sequestering proteins such as calprotectin, metallothioneins, lactoferrin, lipocalin-2, and ceruloplasmin emerge as central regulators of both nutritional immunity and damage-associated signaling.
What was reviewed and who was studied
The paper is a focused review of experimental and observational work on mammalian innate immune responses (primarily neutrophils, monocytes, macrophages, and dendritic cells) to diverse pathogens, including Staphylococcus aureus, Acinetobacter baumannii, Clostridioides difficile, Candida albicans, Aspergillus fumigatus, Helicobacter pylori, Mycobacterium tuberculosis, and Plasmodium spp., under varying availability of zinc, manganese, iron/heme, and copper. It emphasizes phagocyte biology, phagosomal metal flux (“brass dagger”), and metal-binding host proteins in inflamed tissues and blood.
Major findings
| Finding | Details and context |
|---|---|
| Nutritional immunity redistributes metals | Inflammation induces systemic and local restriction of zinc, manganese, and iron, and raises serum copper; metals are concentrated or depleted in phagosomes via transporters (e.g., NRAMP1) and metal pumps, generating metal-replete and metal-deplete niches. |
| Calprotectin and S100 proteins multi-target metal pools | Calprotectin (S100A8/A9) from neutrophils sequesters zinc, manganese, iron, and nickel and limits growth of multiple bacterial and fungal pathogens; S100A7 and S100A12 further shape zinc and copper availability at epithelial and myeloid surfaces. |
| Metallothioneins tune intracellular zinc and macrophage polarization | MT1/MT2 support pro-inflammatory (M1) macrophage responses and pathogen restriction by zinc sequestration, whereas IL-4–induced MT3 increases labile zinc and favors anti-inflammatory (M2) programming and Histoplasma persistence. |
| Iron/heme and hepcidin reshape phagocyte effector pathways | Hepcidin-driven ferroportin blockade causes iron retention in monocytes/macrophages and neutrophils, impairing IFN-γ–inducible genes, iNOS, reactive oxygen species, and NET formation while also limiting erythropoiesis and erythropoietin, thereby sustaining inflammation. |
| Manganese and copper have bidirectional effects | Elevated manganese enhances neutrophil adhesion, degranulation, and killing but can increase susceptibility to systemic S. aureus infection; copper deficiency reduces neutrophil numbers and oxidative burst, whereas copper excess drives excessive ROS, impaired phagocytosis, and increased NETosis and apoptosis. |
| Metal-binding proteins act as DAMPs and opsonins | Calprotectin, metallothioneins, lactoferrin, lipocalin-2, and ceruloplasmin not only sequester metals but also signal through TLRs, RAGE, and other receptors to shape chemotaxis, proliferation, apoptosis, and oxidative damage control, impacting infection and cancer contexts. |
Implications for Microbial Metallomics
The review positions the metallome as a dynamic regulator of phagocyte physiology, where metal gradients and binding proteins simultaneously constrain microbial metal acquisition and reprogram immune effector functions.
| Concept | Implication |
|---|---|
| Phagosomal “brass dagger” (Zn, Cu influx; Fe/Mn/Mg efflux) | Quantifying metal speciation inside phagosomes during infection could link microbicidal metal intoxication to concurrent suppression or support of NADPH oxidase and other host enzymes, refining models of intracellular killing versus persistence. |
| Calprotectin’s multi-metal sequestration and DAMP activity | Measuring calprotectin-bound versus free zinc/manganese near lesions may clarify how S100-driven metal starvation intersects with TLR4/RAGE signaling to tune neutrophil recruitment and NET formation, as summarized in the diagram on page |
| Metallothionein-driven zinc pools in macrophage subsets | Profiling MT isoforms and labile zinc in M1/M2 macrophages could provide functional metallomic markers of tissue-destructive versus reparative inflammation and identify zinc-dependent vulnerabilities in intracellular pathogens such as H. capsulatum. |
| Hepcidin–ferroportin axis and heme catabolism | Integrating iron/heme speciation with transcriptional signatures of macrophage polarization and erythropoietin levels may illuminate when iron-withholding crosses from antimicrobial to immunosuppressive, as depicted in the signaling diagram on page 22. |
| Manganese-enhanced cGAS–STING signaling | Mapping tissue manganese distribution alongside cGAS–STING activation during DNA viral infection or tumor immunity could define metal thresholds that optimize antiviral responses without fostering bacterial exploitation of Mn-rich niches. |
| Plasmodial hemozoin as a heme-derived immune modulator | Differentiating soluble heme, hemozoin-bound heme iron, and host iron pools may help explain how hemozoin accumulation simultaneously impairs phagocytosis, antigen presentation, and PKC activity while driving TNF-α and IL-1β release in severe malaria. |
Limitations
This is a narrative review without systematic search or meta-analysis, so relative weight of individual studies is not formally assessed. Many referenced experiments employ extreme metal supplementation or depletion unlikely to mirror in vivo gradients, limiting direct clinical extrapolation. Quantitative metal concentrations, oxidation states, and spatially resolved metallomics are largely absent, and microbiome-level community effects are only indirectly addressed.
Future perspectives
The authors highlight the need for spatially and temporally resolved measurements of zinc, manganese, iron/heme, and copper during infection to define physiologic metal gradients and their impact on immune cells. Future work should dissect whether immune cells can reclaim metals from host metal-binding proteins, and how bacterial siderophores and transporters remodel local metal landscapes to subvert immunity. Integrated metallomic–transcriptomic profiling of phagocytes, coupled with pathogen metal acquisition mutants, could clarify when metal manipulation primarily benefits host versus microbe and guide host-directed therapies targeting hepcidin, S100 proteins, metallothioneins, or lipocalin-2.
Key takeaways for Researchers and Clinicians
This review synthesizes evidence from animal models, primary human cells, and diverse pathogens showing that inflammatory redistribution of zinc, iron/heme, manganese, and copper in blood, tissues, and phagosomes controls not only microbial growth but also core neutrophil and macrophage functions. The most consistently implicated metals are zinc and iron/heme, with zinc shaping NF-κB, MAPK, and NLRP3 signaling and phagocytosis, and iron/heme—via hepcidin and heme oxygenase-1—restraining iNOS, IFN-γ–inducible genes, and reactive oxygen species while influencing macrophage polarization and erythropoiesis.
Metal redistribution during infection is not merely antimicrobial; it is an active immunomodulator. Clinically, this argues for caution with systemic metal supplementation or chelation, supports targeting hepcidin–ferroportin and S100/metallothionein pathways as adjunctive host-directed therapies, and highlights trace-metal patterns as potential biomarkers of inflammatory state and pathogen niche.
Manganese and copper emerge as bidirectional modifiers: manganese supports neutrophil adhesion, degranulation, and cGAS–STING activation yet can worsen systemic S. aureus infection when dietary levels are high, whereas copper deficiency blunts oxidative burst and excess copper fosters damaging ROS, impaired phagocytosis, and aberrant NETosis. Methodologically, the paper underscores that many data derive from non-physiologic metal extremes and calls for in situ metallomic mapping of infection sites. A central translational message is that “nutritional immunity” is a double-edged sword: therapeutic manipulation of trace metals or their binding proteins must balance starving the microbe with preserving competent, not overdriven, innate immunity.
Citation
Monteith AJ, Skaar EP. The impact of metal availability on immune function during infection. Trends Endocrinol Metab. 2021;32(11):916–928. doi:10.1016/j.tem.2021.08.004