Staphylococcus aureus Metal Acquisition and Nutritional Immunity: Virulence Insights Original paper

What was reviewed?

This review article critically evaluates the mechanisms by which Staphylococcus aureus acquires essential transition metals—specifically iron, manganese, and zinc—despite host-imposed nutritional immunity. The paper also explores host strategies that limit bacterial access to these metals as part of the innate immune response, and how these interactions shape bacterial virulence. It further assesses the physiological and molecular basis of metal ion acquisition, storage, transport, and detoxification systems in S. aureus, with emphasis on their contribution to pathogenicity across various infection models.

Who was reviewed?

The review synthesizes a comprehensive body of work involving both in vitro molecular studies and in vivo animal models, particularly murine abscess and systemic infection models, to elucidate how S. aureus exploits siderophores, heme acquisition systems, and high-affinity metal transporters. Studies involving genetically modified bacterial strains (e.g., mutants lacking isd, mntABC, mntH, or hrtAB) and host knockout models (e.g., calprotectin-deficient mice or Nramp1-deficient mice) are also central to the review’s analysis.

Most Important Findings

Understanding how Staphylococcus aureus circumvents nutritional immunity reveals key mechanistic nodes underpinning its virulence. The organism’s capacity to acquire essential transition metals—iron, manganese, zinc, and copper—via specialized systems allows it to evade host-imposed metal sequestration, enabling persistence in inflamed or nutrient-deprived tissue microenvironments such as abscesses. The host counters this with dynamic sequestration strategies, including proteinaceous chelators like calprotectin and localized oxidative stress. These metal-dependent virulence strategies are not only essential to S. aureus pathogenesis but also shape its metallomic and microbiome signature within infected tissues. Below is a structured summary of these host-pathogen interactions.

Category	Key Findings
Iron Acquisition	S. aureus synthesizes two siderophores—staphyloferrin A and staphyloferrin B—that chelate iron and are imported via HtsABC and SirABC, respectively. Preferential iron acquisition from heme occurs through the Isd system, which involves surface receptors (IsdB, IsdH), membrane transporters (IsdDEF), and cytoplasmic heme oxygenases (IsdG, IsdI). IsdB demonstrates high specificity for human hemoglobin.
Manganese Acquisition	High-affinity manganese uptake is mediated by MntABC (ABC-type) and MntH (Nramp-type) transporters. Manganese is essential for the activity of superoxide dismutases (SodA, SodM), which protect S. aureus against reactive oxygen species.
Zinc and Copper Interactions	Calprotectin sequesters both manganese and zinc in abscesses. While S. aureus zinc importers remain unidentified, export is mediated by CzrAB and plasmid-encoded CadA. Host-derived copper toxicity is countered by S. aureus through CopA (efflux pump) and CopZ (chaperone), regulated by the CsoR repressor.
Host-Microbe Competition	The vertebrate immune system enforces nutritional immunity through sequestration of iron (transferrin, lactoferrin, ferritin), manganese, and zinc (calprotectin). Imaging mass spectrometry and LA-ICPMS confirm localized depletion of manganese and zinc in abscess cores.
Microbiome-Relevant Insights	The tug-of-war between calprotectin and S. aureus defines a manganese- and zinc-centric virulence axis, contributing to microbial persistence and shaping microbiome signatures. The non-redundant roles of IsdG and IsdI across tissue sites suggest adaptive metallomic specialization that could serve as a basis for microbial stratification in disease-specific microbiome signatures.

Key implications

The review underscores that transition metal acquisition is not ancillary but foundational to S. aureus pathogenesis, especially within abscesses where nutritional immunity is most intense. These findings highlight new avenues for antimicrobial strategies, such as siderophore inhibitors, calprotectin mimetics, or vaccines targeting IsdA/IsdB. Furthermore, the dependency on specific metal ions offers microbiome signature implications: differential abundance or gene expression of metal transporters (e.g., mntA, isdB) could serve as microbial biomarkers of invasive staphylococcal disease. Imaging mass spectrometry emerges as a critical tool in microbial metallomics for both diagnostic and therapeutic development.

Citation

Cassat JE, Skaar EP. Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity.Semin Immunopathol. 2012;34(2):215–235. doi:10.1007/s00281-011-0294-4.