Nutritional immunity: the battle for nutrient metals at the host–pathogen interface 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?
The review titled “Nutritional Immunity: The Battle for Nutrient Metals at the Host–Pathogen Interface” by Murdoch and Skaar (2022) provides a comprehensive update on how vertebrate hosts manipulate metal bioavailability to control bacterial infections and how bacterial pathogens counteract these strategies. The authors explore the essential roles of trace metals—iron (Fe), zinc (Zn), manganese (Mn), and copper (Cu)—in bacterial and host physiology and examine how their regulated distribution, sequestration, or overload can determine infection outcomes. The review focuses on molecular mechanisms of host-mediated metal withholding (nutritional immunity), bacterial acquisition strategies, and the evolving arms race over these metals at specific host-pathogen interfaces.
Who was reviewed
This review synthesizes findings across multiple Gram-positive and Gram-negative bacterial pathogens, including Staphylococcus aureus, Salmonella Typhimurium, Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Neisseria meningitidis, among others. Host systems, including neutrophils, macrophages, epithelial cells, and various tissues like the intestinal tract and respiratory mucosa, are reviewed in terms of their specific roles in metal sequestration, intoxication, and immune modulation.
What were the most important findings?
A central conclusion of this review is that nutritional immunity involves both limitation and intoxication of nutrient metals. Hosts utilize proteins like calprotectin, lipocalin-2, transferrin, and metallothioneins to sequester Fe, Zn, Mn, and Cu, thereby starving pathogens of essential cofactors. Simultaneously, immune cells like macrophages and neutrophils deploy excess Zn and Cu to phagosomes, leveraging metal toxicity to kill internalized bacteria.
Bacterial pathogens have evolved diverse counterstrategies: siderophore production for Fe acquisition, zincophores and metallophores for Zn uptake, NRAMP and ABC transporter systems for Mn and Zn, and metallochaperones (e.g., ZigA, ZagA) to distribute metals to target enzymes under stress. Siderophores such as yersiniabactin not only scavenge Fe but also bind Zn and Cu, expanding their functional utility. Some pathogens even pirate host metal-binding proteins like calprotectin, underscoring the evolutionary sophistication of metal acquisition systems.
Pertinent to the microbiome signatures database, the review identifies multiple trace metal acquisition systems and regulators as conditionally expressed virulence determinants. For example, S. aureus relies on the Isd system for heme-Fe acquisition in calprotectin-rich environments, while E. coli expresses stealth siderophores like salmochelin to evade host lipocalin-2. The regulation of metal transporters by Zur, Fur, and MntR points to coordinated responses within microbial communities to host-induced metal stress. These systems may serve as key microbial markers (MMAs) in tissue-specific dysbiosis and inflammation, particularly in gut, respiratory, and skin-associated microbial niches.
What are the greatest implications of this review?
This review reframes trace metals not just as nutrients, but as strategic tools of host defense and bacterial offense. The dual use of metals as essential cofactors and toxic agents presents a unique therapeutic opportunity. Interventions targeting bacterial metal acquisition—such as siderophore-drug conjugates, gallium-based Fe mimetics, or vaccines targeting outer membrane metal receptors—are already in clinical development, as exemplified by the FDA-approved antibiotic cefiderocol. Importantly, these strategies must be balanced to avoid unintended disruption of commensal microbes that rely on similar metalloproteins and uptake systems.
From a microbiome perspective, this review strongly supports the inclusion of metal utilization traits in microbial signature profiling. Shifts in metal acquisition gene expression or the presence of stealth siderophores, metallophores, and specific metalloregulators could distinguish pathogenic from commensal states in host-associated microbial communities. It also emphasizes that dietary metal intake and host genetic variants in metal regulation significantly impact microbiome composition and infection risk. This opens new avenues for personalized dietary or metallomic interventions in microbiome modulation and pathogen control.