Uncategorized
Nutritional Immunity and Trace Metals in Infection Care
Clinical Overview
This narrative review synthesizes current knowledge on how vertebrate hosts and bacterial pathogens compete for iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), and gallium (Ga) during infection. It focuses on vertebrate tissues (blood, mucosa, lung, gut) and major bacterial pathogens such as Staphylococcus aureus, Acinetobacter baumannii, Mycobacterium tuberculosis, Salmonella enterica, Neisseria spp., and Pseudomonas aeruginosa across in vitro and in vivo models. Host systems restrict Fe(III)/Fe(II), Zn(II), and Mn(II) through transporters and metal-binding proteins (transferrin, lactoferrin, calprotectin, S100A7/A12, NGAL, metallothioneins), while selectively delivering toxic Cu(I)/Cu(II) and Zn(II) into phagosomes for microbial killing. Pathogens counter with high-affinity uptake systems (Isd, ZnuABC/ZnuD, MntABC/MntH, FeoB), metallophores (siderophores, “zincophores”), metallochaperones, export pumps, and virulence programs tuned to metal stress. Therapeutic concepts include siderophore–antibiotic conjugates and Ga(III) as a Fe(III) mimic.
What was reviewed and who was studied
The paper is a mechanistic review of “nutritional immunity,” integrating data from animal models, human genetic conditions, and in vitro studies to describe how vertebrate hosts and diverse bacterial pathogens regulate Fe, Zn, Mn and Cu during infection. It spans mucosal, systemic, and intracellular niches, emphasizing immune cells (neutrophils, macrophages), epithelial barriers, and the gut microbiota.
Major findings
| Domain | Finding |
|---|---|
| Iron restriction and acquisition | Host Fe is largely locked in haemoglobin, haem, transferrin and ferritin; hepcidin–ferroportin regulation and NRAMP1 deprive pathogens of Fe(II)/Fe(III). Pathogens counter with haemolysins, haem uptake systems (Isd, Phu/Has, haemophores), Fe(III) siderophores, and Fe(II) transport via FeoB and alternative ferrous importers. |
| Siderophore and xenosiderophore ecology | >500 siderophores enable Fe(III) scavenging with higher affinity than transferrin/lactoferrin, and pathogens often use multiple siderophores plus xenosiderophores and even neurotransmitters as Fe sources, yielding spatially heterogeneous siderophore production in vivo.41579_2022_Article_745 |
| Zn/Mn sequestration by host S100 proteins | Calprotectin (S100A8/A9), S100A7 and S100A12 sequester Zn(II), Mn(II), Ni(II) and Fe(II/III), particularly at neutrophil-rich and epithelial sites, profoundly limiting metal availability to pathogens and reshaping commensal communities. The diagram on page 6 shows Zn/Mn flows through ZIP/ZnT transporters and S100 proteins. |
| Bacterial Zn/Mn uptake and metallophores | Pathogens deploy ZnuABC/ZnuD, AdcABC, MntABC/MntH, outer membrane channels (MnoP), and metallophores such as staphylopine, yersiniabactin, coelibactin and pseudopaline to acquire Zn(II)/Mn(II), including from host calprotectin and S100A7. T6SS-dependent exporters (YezP, TseZ, TseM) deliver metal-binding effectors to support oxidative stress resistance. |
| Metal intoxication in phagocytes | Macrophages and neutrophils actively load phagosomes with Cu(II)/Cu(I) (via CTR1–ATOX1–ATP7A) and Zn(II) (via ZIP8/ZNT1 and zincosomes), driving mis-metalation, Fe–S cluster disruption and metabolic collapse in bacteria. Bacterial P-type ATPases (CopA, CadA, ZntA, CzcD), RND efflux systems and metallothioneins (MymT, SmtA/BmtA) counteract this. The schematic on page 8 visualizes these fluxes. |
| Diet, host genetics and therapeutics | Fe overload states (β-thalassemia, haemochromatosis) and high dietary Fe/Zn/Mn predispose to specific infections, while deficiencies increase susceptibility via impaired immunity. Therapies in development include Ga(III) as a Fe(III) mimic, siderophore–antibiotic conjugates (cefiderocol), FeoB inhibitors, and vaccines/antibodies targeting metal receptors (IsdA/B, ZnuD). |
Implications for Microbial Metallomics
The review places dynamic metal pools and speciation in host tissues and bacterial cells at the centre of infection biology, arguing that metal fluxes define both microbial physiology and immune effector function.
| Concept | Implication |
|---|---|
| Fe sequestration vs siderophore/haem piracy | Quantifying Fe(III)/Fe(II) pools and haem-bound Fe across tissues, alongside siderophore and haem receptor expression, could resolve niche-specific Fe limitation and identify windows where Fe-mimetic therapeutics (e.g. Ga(III)) are most effective. |
| S100-mediated Zn/Mn deprivation | Calprotectin and S100A7/A12 sharply remodel Zn(II)/Mn(II) availability; metallomic profiling around neutrophil-rich foci could link specific Zn/Mn gradients to pathogen survival strategies and microbiome shifts in gut and skin. |
| Metallophores as multi-metal ligands | Siderophores such as yersiniabactin scavenge Zn(II) and Cu(II) as well as Fe(III), suggesting that “metallophore signatures” might serve as biomarkers of multi-metal stress and targets for broad-spectrum chelator or antibody design. |
| Cu/Zn intoxication microdomains | Restricting toxic Cu/Zn bursts to phagosomes protects host tissue while killing microbes; spatially resolved metallomics of phagolysosomes versus cytosol would clarify how metal intensities and redox states correlate with bacterial fate. |
| Metallochaperones and metal prioritization | Proteins such as ZigA/ZagA (COG0523) likely direct scarce Zn(II) to essential enzymes; identifying their client metalloproteins in vivo would define a “priority metallome” under host-imposed metal starvation. |
| Diet/genetic perturbations and microbiome metal ecology | The Box 1 discussion implies that dietary metals and host iron-handling polymorphisms alter microbiota structure and pathogen expansion; integrating faecal metal speciation with microbial community data could refine risk stratification and dietary guidance. |
Limitations
This is a narrative, mechanistic review rather than a systematic or meta-analytic synthesis and provides limited quantitative data on metal concentrations or speciation in human tissues. Many mechanistic insights derive from murine or in vitro models and a subset of pathogens. The review mentions but does not detail analytical metallomics platforms, and human clinical biomarker data remain sparse.
Future perspectives
The authors highlight major gaps: uncharacterized host siderophore-binding proteins, undiscovered non-Fe metallophores, and unclear kinetics of metal allocation within pathogens under immune pressure. Future work logically includes defining compartmental metal pools at high spatial and temporal resolution, mapping metallochaperone networks and their client enzymes during infection, and dissecting how metal and non-metal nutrient limitation intersect in vivo. Therapeutically, rational design of Fe(III)/Ga(III)-mimetic conjugates, metal-transporter–targeted vaccines, and host-directed modulation of transferrin, S100 proteins or hepcidin emerge as tractable extensions of current data.
Key takeaways for Researchers and Clinicians
This review synthesizes vertebrate–bacterial interactions across gut, respiratory, skin, blood and intracellular compartments, focusing on pathogens such as S. aureus, A. baumannii, M. tuberculosis, Salmonella spp. and Neisseria spp. The metals that matter most are Fe(III)/Fe(II), Zn(II), Mn(II) and Cu(I)/Cu(II), with emerging roles for Ga(III) as a therapeutic Fe(III) mimic. The clearest associations link host Fe/Zn/Mn restriction or Cu/Zn intoxication to reduced pathogen load and attenuated virulence in animal models, particularly where deletion of uptake (Isd, ZnuABC/ZnuD, MntABC/MntH, FeoB) or detoxification systems (CopA, ZntA, CzcD, metallothioneins) causes marked loss of fitness.
Methodologically, the paper underscores that transporters, metallophores and metallochaperones are both readouts and levers of metal stress, making them attractive targets for drugs, antibodies and vaccines. A succinct translational hook is that infection outcome can often be reframed as a metal allocation problem, in which tipping Fe/Zn/Mn/Cu balance at specific host–pathogen interfaces may improve diagnostics, risk stratification and antimicrobial therapy.
The review frames trace-metal management as a druggable axis of host defence and bacterial virulence, pointing toward diagnostics based on metal–microbe signatures and therapies that either reinforce host metal sequestration/intoxication or selectively disrupt bacterial metal uptake and detoxification.
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