A Gram-negative bacterium that spans the commensal-pathogen spectrum, with pathogenic variants (UPEC, STEC, EHEC) deploying nickel-dependent enzymes as virulence factors. E. coli is the model organism for nickel transport biology -- the NikABCDE system was first characterized here -- and pathogenic strains have co-opted nickel metabolism for urinary tract colonization, gut survival, and acid resistance.
Metal-Dependent Virulence Factors
[NiFe] Hydrogenases
E. coli encodes multiple [NiFe] hydrogenases [maier 2019 nickel microbial pathogenesis]:
- Hyd-1 (HyaABC): membrane-bound, H2-uptake. Expressed under aerobic/microaerobic conditions.
- Hyd-2 (HybOABC): membrane-bound, H2-uptake. Most active under anaerobic conditions with alternative electron acceptors.
- Hyd-3 (HycBCDEFG): cytoplasmic, H2-evolving. Part of the formate hydrogenlyase (FHL) complex; produces H2 during mixed-acid fermentation.
- Hyd-4 (HyfABCDEFGHIR): second FHL-associated complex.
- In pathogenic E. coli, hydrogenases provide:
- Respiratory flexibility in the oxygen-variable gut environment.
- Acid resistance: Hyd-3/FHL consumes formate and produces H2 + CO2, removing acidic fermentation products.
- Energy generation in nutrient-limited intracellular niches (for UPEC inside bladder epithelial cells).
Urease (in Shiga Toxin-Producing E. coli)
- STEC/EHEC strains use urease for acid survival during gastric transit [maier 2019 nickel microbial pathogenesis].
- Urease-mediated ammonia production buffers pH, enabling survival through the stomach to reach the intestinal colonization site.
- Not all E. coli pathotypes carry urease -- it is primarily found in STEC and some UPEC strains.
Ni-Acireductone Dioxygenase (ARD)
- Part of the methionine salvage pathway; the Ni-bound form is present in E. coli and other gamma-proteobacteriaceae.
- Provides metabolic flexibility depending on available metal cofactors.
Fe-Dependent Virulence
- Enterobactin: the canonical high-affinity siderophore (Ka for Fe3+ = ~10^52).
- Aerobactin: found in many UPEC and invasive strains; functions at lower affinity but under a broader range of conditions.
- Yersiniabactin: see below -- dual iron/nickel role.
- ChuA/Chu system: heme uptake receptor in EHEC and UPEC.
- Shiga toxin expression is iron-regulated (repressed by Fur under high iron; induced under iron limitation).
Metal Acquisition Systems
NikABCDE -- The Model Nickel Transporter
- First characterized Ni-specific ABC transporter [maier 2019 nickel microbial pathogenesis].
- NikA: periplasmic Ni-binding protein.
- NikB/NikC: integral membrane permease subunits.
- NikD/NikE: ATP-binding cassette subunits providing energy.
- Regulated by NikR (nickel-responsive repressor) -- under high Ni, NikR represses nikABCDE to prevent toxicity.
- This system is the paradigm for understanding nickel import across all bacteria; homologs found in salmonella typhimurium, helicobacter pylori (NiuBDE), and many other pathogens.
Yersiniabactin -- A Dual Iron/Nickel Metallophore
- Originally characterized as an iron siderophore in Yersinia pestis, but the UPEC yersiniabactin also binds extracellular nickel [maier 2019 nickel microbial pathogenesis].
- In uropathogenic E. coli, yersiniabactin serves a dual role:
- Iron acquisition for growth.
- Nickel import for hydrogenase/urease metalation during UTI.
- Nickel transport via yersiniabactin is upregulated during urinary tract infection, suggesting active nickel scavenging in the urinary environment.
- This dual-specificity metallophore represents a metabolically efficient strategy: one molecule, two essential metals.
Hydrogenase Maturation
- HypABCDEF: accessory proteins for [NiFe] active site assembly, shared across all four hydrogenases.
- HypB is a GTPase/nickel metallochaperone; HypA delivers nickel to HypB.
Nutritional Immunity Evasion
- Lipocalin-2: host protein that sequesters enterobactin-Fe complexes. UPEC strains carrying yersiniabactin or salmochelin evade lipocalin-2.
- Calprotectin: sequesters Zn, Mn, and Ni at infection sites.
- Lactoferrin: sequesters iron in mucosal secretions and urine.
- UPEC nickel transport upregulation during UTI suggests the pathogen senses host-mediated nickel restriction and responds with increased scavenging.
Disease Associations
- Urinary tract infections (UTI): UPEC is the #1 cause of community-acquired UTI; nickel transport upregulated during infection.
- Hemolytic uremic syndrome (HUS): STEC/EHEC (O157:H7); Shiga toxin is iron-regulated.
- Neonatal meningitis: K1 capsular strains.
- Traveler's diarrhea: ETEC strains.
- Crohn's disease-associated: adherent-invasive E. coli (AIEC) in the ileum.
- Bacteremia/sepsis: from urinary or GI source.
Connection to Environmental Metal Exposure
- Dietary nickel excreted in urine provides substrate for UPEC nickel scavenging during UTI -- higher dietary nickel may theoretically support UPEC virulence.
- Gut E. coli populations are exposed to dietary metals; iron supplementation is known to promote pathogenic E. coli expansion in the gut.
- Yersiniabactin's dual iron/nickel specificity means environmental iron AND nickel both feed UPEC metal acquisition.
- Agricultural metal contamination selects for metal-tolerant E. coli in food-animal production.
Connections
- metal dependent virulence -- [NiFe] hydrogenases, STEC urease, yersiniabactin dual Fe/Ni metallophore
- nickel -- NikABCDE is the paradigmatic nickel transporter; yersiniabactin also scavenges Ni
- iron -- enterobactin, aerobactin, yersiniabactin; Shiga toxin is iron-regulated
- salmonella typhimurium -- closely related; shares NikABCDE architecture and multiple hydrogenases
- helicobacter pylori -- NiuBDE is homologous to NikABCDE
- proteus mirabilis -- both cause UTI with nickel-dependent virulence mechanisms
- nutritional immunity -- lipocalin-2 and calprotectin counteract E. coli metal acquisition
- staphylococcus aureus -- yersiniabactin (Ni-binding) parallels staphylopine (Ni-binding)