Nutritional Immunity (Metal Sequestration)

General Principle#

Pathogens require metal cofactors for virulence enzymes.^{[1]Robinson & Glasfeld 2020 — Metalation and Mis-metalation: Nature's Challenge in Metal CoordinationNigel J. Robinson, Andrea Glasfeld · 2020Open reference 1 ↓} Hosts sequester these metals using binding proteins, lowering free metal availability at infection sites.^{[2]Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the GutSummer D Bushman, Eric P Skaar, N Luisa Hiller · 2025Open reference 2 ↓} This is an innate immune mechanism—part of the "nutritional immunity" concept.

Best characterized for iron (ferritin, transferrin, lactoferrin, hepcidin, NRAMP1) and zinc/manganese (calprotectin).^{[3]Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional ImmunityJames E. Cassat, Eric P. Skaar · 2012Open reference 3 ↓[2]Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the GutSummer D Bushman, Eric P Skaar, N Luisa Hiller · 2025Open reference 2 ↓}

Dual strategy: Hosts both withhold metals (restriction) and flood pathogens with toxic metal levels (intoxication).

Macrophages pump copper (Cu) (>500 uM) and zinc (Zn) into phagolysosomes to kill engulfed bacteria, and PGRPs induce 60-100x intracellular zinc/copper increases in target cells.^{[4]Kashyap et al. 2014 — Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal StressDipika R. Kashyap, Minhui Wang, Li-Hung Liu et al. · 2014Open reference 4 ↓[2]Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the GutSummer D Bushman, Eric P Skaar, N Luisa Hiller · 2025Open reference 2 ↓}

Mis-metallation is the killing mechanism: zinc flooding mis-metalates the PerR regulator in Gram-positive pathogens, causing heme toxicity and oxidative death.^{[5]Chandrangsu & Helmann 2016 — Intracellular Zn Intoxication Mis-metalates PerR, Causing Heme Toxicity and Oxidative DeathPete Chandrangsu, John D. Helmann · 2016Open reference 5 ↓}

Chelating either zinc or copper completely abolishes PGRP bactericidal activity, confirming metal intoxication is required, not incidental.^{[4]Kashyap et al. 2014 — Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal StressDipika R. Kashyap, Minhui Wang, Li-Hung Liu et al. · 2014Open reference 4 ↓}

Why Nickel is a Good Target#

Mammals do not synthesize known nickel (Ni)-requiring proteins—so restricting nickel imposes no cost on the host. Nickel is already scarce in mammalian tissues: <5 ppm in most organs, <0.1% of zinc levels. Many important pathogens (Helicobacter pylori, Staphylococcus aureus, Salmonella, *Brucella*) depend on nickel-enzymes (Urease, Hydrogenase) for virulence.

Host Proteins Involved#

Calprotectin (S100A8/A9): neutrophil-derived; >1 mg/mL at infection sites.^{[2]Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the GutSummer D Bushman, Eric P Skaar, N Luisa Hiller · 2025Open reference 2 ↓} Canonically sequesters manganese (Mn) and zinc (Zn) to starve S. aureus of manganese-SOD cofactors.^{[3]Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional ImmunityJames E. Cassat, Eric P. Skaar · 2012Open reference 3 ↓[6]Martin & Waters 2022 — Manganese Homeostasis, Stress, and Pathogenesis in BacteriaJulia E. Martin, Lauren S. Waters · 2022Open reference 6 ↓}

Recent finding: also coordinates nickel (Ni)(II) at the hexahistidine site preferentially over zinc(II), sequestering nickel from S. aureus and K. pneumoniae and inhibiting their urease activity.^{[7]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 7 ↓}

In response, S. aureus activates the small RNA RsaC to suppress manganese-dependent SodA translation, freeing scarce manganese for other essential processes.^{[8]McFarlane 2025 — A Manganese-Sparing Response Balances Competing Cellular Demands to Enable Staphylococcus aureus InfectionRiley A McFarlane, Jana N Radin, Rafat Mazgaj et al. · 2025Open reference 8 ↓}

Lactoferrin: primarily known for iron binding via bi-lobal transferrin fold; Histidine/tyrosine ligands can also bind nickel.^{[7]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 7 ↓} Nickel-sequestering effect is plausible but unstudied.

Transferrin: serum iron carrier that restricts iron availability to extracellular pathogens; exploited by siderophore-producing Enterobacteriaceae.^{[2]Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the GutSummer D Bushman, Eric P Skaar, N Luisa Hiller · 2025Open reference 2 ↓}

Hepcidin: master regulator of iron homeostasis that degrades ferroportin and induces functional iron restriction during infection.^{[2]Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the GutSummer D Bushman, Eric P Skaar, N Luisa Hiller · 2025Open reference 2 ↓} Role in nickel restriction unknown but likely given overlap in metal handling.

NRAMP1 (SLC11A1): divalent metal transporter in macrophage phagolysosomes. Can export nickel(II), restricting availability to engulfed intracellular pathogens.^{[7]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 7 ↓}

Peptidoglycan Recognition Proteins (PGRPs): Kill bacteria by inducing 60-100x intracellular zinc(II) and copper (Cu)+, synergistically with Oxidative Stress and glutathione depletion. Metal intoxication is a required component of killing.^{[4]Kashyap et al. 2014 — Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal StressDipika R. Kashyap, Minhui Wang, Li-Hung Liu et al. · 2014Open reference 4 ↓}

Pathogen Counter-Strategies#

Pathogens have evolved elaborate systems to overcome nickel scarcity. High-affinity transporters: ABC-type (NikABCDE, NiuBDE), NiCoT-type (NixA), ECF-type. Metallophores (nickel-scavenging small molecules).

Staphylopine (S. aureus): nicotianamine-like, broad-spectrum metal chelator.

Pseudopaline (P. aeruginosa): primary nickel acquisition mechanism. Yersiniabactin (E. coli, Klebsiella, Yersinia): originally iron siderophore, also binds nickel. Storage proteins: Hpn/HpnI in H. pylori—buffer against nickel fluctuations.

Efficient recycling: some pathogens recycle nickel from metallophore complexes.

Therapeutic Potential#

Targeting nickel availability is proposed as a therapeutic strategy.^{[7]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 7 ↓} Block nickel trafficking pathways in pathogens. Enhance host nickel sequestration.

Complication: disrupting nickel for pathogens could also affect the (nickel (Ni)-utilizing) commensal microbiota → potential Dysbiosis.

The Two-Kingdom Conundrum#

An evolutionary puzzle. Plants use nickel (nickel (Ni)-urease is widespread) and naturally compete with pathogens for it. Mammals don't use nickel, so sequestration is "free"—no self-harm.

Yet very few plant pathogens use nickel (only Streptomyces scabies and relatives).

This asymmetry remains unexplained.