Role of Nickel in Microbial Pathogenesis Original paper
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Metals
Metals
OverviewHeavy metals play a significant and multifaceted role in the pathogenicity of microbial species. Their involvement can be viewed from two primary perspectives: the toxicity of heavy metals to microbes and the exploitation of heavy metals by microbial pathogens to establish infections and evade the host immune response. Understanding these aspects is critical for both […]
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Karen Pendergrass
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was reviewed?
This comprehensive review article by Maier and Benoit (2019) explores the role of nickel as a critical cofactor in microbial pathogenesis, detailing its involvement in virulence-related enzymes and systems across a broad range of prokaryotic and eukaryotic pathogens. The review synthesizes decades of experimental findings regarding nickel-dependent enzymes—primarily urease and [NiFe]-hydrogenase—and their roles in microbial survival, colonization, biofilm formation, and host damage. Additionally, the authors examine nickel uptake systems, transporters, metallochaperones, storage proteins, and host immune mechanisms that attempt to limit nickel availability through nutritional immunity. The paper also emphasizes the dual nature of nickel as both a microbial nutrient and a potential antimicrobial target, especially in pathogens that rely on Ni-enzymes for virulence.
Who was reviewed?
The review includes a detailed catalog of more than 40 prokaryotic and nine eukaryotic pathogens harboring nickel-requiring enzymes. These include Helicobacter pylori, Staphylococcus aureus, Salmonella Typhimurium, Proteus mirabilis, Campylobacter jejuni, and Cryptococcus neoformans, among others. The review discusses these organisms in the context of their nickel metabolic strategies, virulence mechanisms, and interactions with host environments.
What were the most important findings?
The most significant finding is that nickel acts as a vital cofactor for several enzymes directly implicated in pathogenesis. Urease and [NiFe]-hydrogenase, the two primary nickel-dependent enzymes, enable microbial survival in hostile (especially acidic) environments and provide essential metabolic advantages during host colonization. For instance, in H. pylori, urease is essential for stomach colonization and contributes to carcinogenesis by promoting angiogenesis and chronic inflammation. Similarly, S. aureus upregulates urease genes in biofilms and uses the enzyme for kidney persistence. P. mirabilis utilizes urease to form crystalline catheter biofilms that enhance infection. Additionally, [NiFe]-hydrogenases in S. Typhimurium and C. jejuni are shown to fuel ATP production via hydrogen oxidation, aiding in host colonization and immune evasion.
The review also highlights that nickel availability is highly restricted in host tissues, leading pathogens to develop sophisticated acquisition systems such as NikABCDE and NixA transporters, metallophores (e.g., staphylopine, pseudopaline), and histidine-rich chaperones like HypB. Host defense mechanisms—including calprotectin, lactoferrin, and potentially hepcidin—attempt to sequester nickel and inhibit Ni-enzyme activation, with successful outcomes in some models.
From a microbiome perspective, commensal microbes such as urease-positive Bifidobacterium, Lactobacillus, and methanogenic archaea also utilize nickel enzymes, suggesting that systemic nickel depletion or chelation strategies could disrupt microbial homeostasis. This raises an important consideration: while nickel-targeted therapies might inhibit pathogens, they could also cause dysbiosis if not carefully balanced.
What are the greatest implications of this review?
The key implication is that nickel metabolism represents both an Achilles’ heel and a strategic fulcrum for pathogenic microbes. The clear reliance of multiple pathogens on nickel-dependent enzymes opens avenues for antimicrobial development, particularly through chelation therapies, targeted inhibition of Ni-enzyme maturation, or interference with nickel import systems. However, this also necessitates caution: beneficial microbes within the host microbiota depend on similar enzymes, and indiscriminate nickel disruption could lead to dysbiosis, undermining long-term host resilience.
For the microbiome signatures database, this review reinforces the value of including nickel-metabolism genes or Ni-enzyme prevalence in microbial trait profiling. For instance, the consistent enrichment of urease-positive pathogens in urinary tract infections and their association with stone formation could serve as microbiome-level markers. Moreover, the presence of nickel-dependent hydrogenases in enteric pathogens suggests a link between dietary nickel intake, microbial virulence, and gut ecosystem dynamics. Clinicians using microbiome data should be aware that modulating dietary nickel or applying nickel-targeted interventions could shift the microbial landscape significantly, both positively and negatively.