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.
- Hosts sequester these metals using binding proteins, lowering free metal availability at infection sites.
- This is an innate immune mechanism — part of the "nutritional immunity" concept.
- Best characterized for iron (ferritin, transferrin, lactoferrin, hepcidin, NRAMP1) and zinc (calprotectin).
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. Recent finding: coordinates Ni(II) at the hexahistidine site preferentially over Zn(II). Sequesters nickel from S. aureus and K. pneumoniae, inhibiting their urease activity.
- Lactoferrin: primarily known for iron binding, but histidine/tyrosine ligands can also bind nickel. Nickel-sequestering effect is plausible but unstudied.
- Hepcidin: master regulator of iron homeostasis. 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.
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 [maier 2019 nickel microbial pathogenesis]:
- 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
- nickel — the metal being sequestered
- helicobacter pylori — most nickel-dependent human pathogen
- oxidative stress — macrophage killing involves both ROS and metal restriction