A gastric pathogen that is arguably the most nickel-dependent human pathogen known. Two of its key virulence factors — urease and [NiFe] hydrogenase — require nickel, and the bacterium has evolved an elaborate nickel trafficking, storage, and regulation system to support them.
Nickel-Dependent Virulence Factors
Urease
- Up to 10% of total proteome.
- Essential for in vivo survival: hydrolyzes urea → ammonia + bicarbonate, buffering cytoplasmic pH to near-neutral in the acidic microenvironment of the stomach.
- Roles beyond acid neutralization [1]:
- Required for persistence even at neutral gastric pH.
- Promotes angiogenesis.
- Stimulates pro-inflammatory cytokines (neutrophil/monocyte chemotaxis).
- Binds Class II MHC on gastric epithelial cells → induces apoptosis.
- Disrupts epithelial tight junctions (via ammonia production → myosin activation).
- Activates blood platelets (lipoxygenase-mediated pathway).
- Alters mucin gene expression.
- Holo-urease (Ni-bound): catalytic urea hydrolysis + non-catalytic oxidant quenching (Met/Met-sulfoxide cycle with MSR repair).
- Apo-urease (Ni-free): retains only oxidant-quenching activity.
- Only 2-25% of urease is actually nickel-activated; the rest may serve the antioxidant role.
[NiFe] Hydrogenase
- Single H₂-uptake type (hydABCDE operon).
- H₂ is chronically available in the stomach (dissolved H₂ ~80 μM; enzyme Km ~1.8 μM — always saturated).
- Powers CagA translocation: the carcinogenic effector. Hydrogenase deletion mutants cannot translocate CagA and do not induce gastric cancer in gerbils.
- Enables H₂-stimulated CO₂ fixation (mixotrophy) — a growth mode never before described in a human pathogen.
- Strains from cancer patients have higher hydrogenase activity than gastritis-only strains.
Nickel Trafficking System
Transport
- NiuBDE (ABC-type): the only transporter operating at both acidic and neutral pH. Can also transport cobalt/bismuth (relevant to bismuth-based eradication therapy).
- NixA (NiCoT-type): secondary, Ni-only. Required in vivo (nixA mutants cannot colonize mouse stomachs) but nixA mutants retain some colonization in other models.
- TonB-dependent FrpB4 for outer membrane transport.
Storage
- Hpn: 47% histidine, 20-mer binding 5 Ni(II)/monomer. Present in all gastric Helicobacter. Primary nickel reservoir.
- HpnI (Hpn-like): 25% histidine. Restricted to H. pylori and H. acinonychis.
- Both compete for nickel under limiting conditions.
- Recent discovery: storage proteins interact with a wide array of metabolic proteins — AmiE (aliphatic amidase), PepA (aminopeptidase), and maturation proteins. Suggests a central hub role in nickel metabolism far beyond simple storage.
Regulation
- NikR: nickel-responsive transcriptional regulator controlling urease and hydrogenase expression.
- Fur: iron-responsive regulator that also influences hyd gene expression.
Export
- CznABC: cobalt-zinc-nickel efflux pump. Critical for nickel homeostasis and in vivo colonization.
Clinical Significance
- Infects ~50% of the global population.
- Causes gastritis, peptic ulcers, gastric adenocarcinoma, MALT lymphoma.
- Eradication therapy often includes bismuth — which competes with nickel transport via NiuBDE [1].
- HspA (GroES homolog with His-rich Ni-binding C-terminus) has been explored as a vaccine candidate — partial protection in mice via intranasal administration.
Connections
- metal dependent virulence — Ni-urease and [NiFe]-hydrogenase are the paradigmatic metal-dependent virulence factors
- nickel — essential cofactor for its two main virulence factors
- nutritional immunity — host calprotectin/lactoferrin may restrict nickel availability
- metal carcinogenesis — H. pylori-mediated gastric cancer is linked to hydrogenase-powered CagA translocation
- gastric cancer — H. pylori is the primary causative organism; nickel-dependent metalloenzymes power the cancer cascade
- gerd — controversial relationship; H. pylori eradication may worsen reflux in some patients [2] [3] [4]
- Contrast with [5]: nickel causes cancer in host cells via epigenetics, while in H. pylori it enables cancer via CagA