Nutritional Immunity (Metal Sequestration)

The strategy by which mammalian hosts withhold essential metals from invading pathogens to limit their growth. Well-established for iron and zinc; underexplored but potentially powerful for nickel.

General Principle

  • Pathogens require metal cofactors for virulence enzymes [1].
  • Hosts sequester these metals using binding proteins, lowering free metal availability at infection sites [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], [2].
  • Dual strategy: Hosts both withhold metals (restriction) and flood pathogens with toxic metal levels (intoxication). Macrophages pump Cu (>500 uM) and Zn into phagolysosomes to kill engulfed bacteria, and PGRPs induce 60-100x intracellular Zn/Cu increases in target cells [4], [2].
  • Mis-metallation is the killing mechanism: Zn flooding mis-metalates the PerR regulator in Gram-positive pathogens, causing heme toxicity and oxidative death [5]. Chelating either Zn or Cu completely abolishes PGRP bactericidal activity, confirming metal intoxication is required, not incidental [4].

Nickel Sequestration [[maier-2019-nickel-microbial-pathogenesis]]

Why Nickel is a Good Target

  • Mammals do not synthesize known 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 Ni-enzymes (urease, hydrogenase) for virulence.

Host Proteins Involved

  • Calprotectin (S100A8/A9): neutrophil-derived; >1 mg/mL at infection sites [2]. Canonically sequesters Mn and Zn to starve S. aureus of Mn-SOD cofactors [3], [6]. Recent finding: also coordinates Ni(II) at the hexahistidine site preferentially over Zn(II), sequestering nickel from S. aureus and K. pneumoniae and inhibiting their urease activity [7]. In response, S. aureus activates the small RNA RsaC to suppress Mn-dependent SodA translation, freeing scarce Mn for other essential processes [8].
  • Lactoferrin: primarily known for iron binding via bi-lobal transferrin fold; histidine/tyrosine ligands can also bind nickel [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].
  • Hepcidin: master regulator of iron homeostasis that degrades ferroportin and induces functional iron restriction during infection [2]. Role in nickel restriction unknown but likely given overlap in metal handling.
  • NRAMP1 (SLC11A1): divalent metal transporter in macrophage phagolysosomes. Can export Ni(II), restricting availability to engulfed intracellular pathogens [7].
  • Peptidoglycan Recognition Proteins (PGRPs): Kill bacteria by inducing 60-100x intracellular Zn2+ and Cu+, synergistically with oxidative stress and glutathione depletion. Metal intoxication is a required component of killing [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]:

  • Block nickel trafficking pathways in pathogens.
  • Enhance host nickel sequestration.
  • Complication: disrupting nickel for pathogens could also affect the (Ni-utilizing) commensal microbiota → potential dysbiosis.

The Two-Kingdom Conundrum

An evolutionary puzzle:

  • Plants use 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.

Connections

References (11)

  1. Nigel J. Robinson, Andrea Glasfeld (2020). Robinson & Glasfeld 2020 — Metalation and Mis-metalation: Nature's Challenge in Metal Coordination. Journal of Biological Inorganic Chemistry. doi:10.1007/s00775-020-01790-3
  2. Summer D Bushman, Eric P Skaar, N Luisa Hiller (2025). Bushman 2025 — The Exploitation of Nutrient Metals by Bacteria for Survival and Infection in the Gut. PLOS Pathogens
  3. ★James E. Cassat, Eric P. Skaar (2012). Metal Ion Acquisition in Staphylococcus aureus: Overcoming Nutritional Immunity. Seminars in Immunopathology. doi:10.1007/s00281-011-0294-4
  4. Dipika R. Kashyap, Minhui Wang, Li-Hung Liu et al. (2014). Kashyap et al. 2014 — Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal Stress. PLoS Pathogens. doi:10.1371/journal.ppat.1004280
  5. Pete Chandrangsu, John D. Helmann (2016). Chandrangsu & Helmann 2016 — Intracellular Zn Intoxication Mis-metalates PerR, Causing Heme Toxicity and Oxidative Death. PLoS Genetics. doi:10.1371/journal.pgen.1006515
  6. Julia E. Martin, Lauren S. Waters (2022). Martin & Waters 2022 — Manganese Homeostasis, Stress, and Pathogenesis in Bacteria. Frontiers in Molecular Biosciences. doi:10.3389/fmolb.2022.945724
  7. ★Robert J. Maier, Stéphane L. Benoit (2019). Role of Nickel in Microbial Pathogenesis. Inorganics. doi:10.3390/inorganics7070080
  8. Riley A McFarlane, Jana N Radin, Rafat Mazgaj et al. (2025). McFarlane 2025 — A Manganese-Sparing Response Balances Competing Cellular Demands to Enable Staphylococcus aureus Infection. mBio
  9. Deenah Osman, Andrew W. Foster, Junjun Chen et al. (2017). Osman et al. 2017 — Fine Control of Metal Concentrations Is Necessary for Cells to Discern Zinc from Cobalt. Nature Communications. doi:10.1038/s41467-017-02085-z
  10. Bart A. Eijkelkamp, Jacqueline R. Morey, Stephanie L. Neville et al. (2014). Eijkelkamp et al. 2014 — Extracellular Zinc Competitively Inhibits Manganese Uptake in Streptococcus pneumoniae. PLoS ONE. doi:10.1371/journal.pone.0089427
  11. Stephanie L. Neville, Jacqueline R. Morey, Erin B. Gillen et al. (2020). Neville et al. 2020 — Cadmium Stress Dictates Central Carbon Flux and Alters Membrane Composition in Streptococcus pneumoniae. Communications Biology. doi:10.1038/s42003-020-01417-y

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