Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity

Cassat, James E.; Skaar, Eric P.

doi:10.1007/s00281-011-0294-4

Cited by 121 publications

(121 citation statements)

References 233 publications

(244 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…While metals such as Fe and Mn are kept away from bacteria to weaken these invading pathogens, the host appears to leverage the antimicrobial properties of Cu to increase the killing power of phagocytes (10,18,27,(68)(69)(70)(71)(72). The complexity of the relationship between metals and infection is emphasized by the dual roles of Zn, which is both restricted to control bacterial growth and harnessed for its toxicity (10,14,51).…”

Section: Figmentioning

confidence: 99%

MntABC and MntH Contribute to Systemic Staphylococcus aureus Infection by Competing with Calprotectin for Nutrient Manganese

et al. 2013

Self Cite

View full text Add to dashboard Cite

During infection, vertebrates limit access to manganese and zinc, starving invading pathogens, such as Staphylococcus aureus, of these essential metals in a process termed "nutritional immunity." The manganese and zinc binding protein calprotectin is a key component of the nutrient-withholding response, and mice lacking this protein do not sequester manganese from S. aureus liver abscesses. One potential mechanism utilized by S. aureus to minimize host-imposed manganese and zinc starvation is the expression of the metal transporters MntABC and MntH. We performed transcriptional analyses of both mntA and mntH, which revealed increased expression of both systems in response to calprotectin treatment. MntABC and MntH compete with calprotectin for manganese, which enables S. aureus growth and retention of manganese-dependent superoxide dismutase activity. Loss of MntABC and MntH results in reduced staphylococcal burdens in the livers of wild-type but not calprotectin-deficient mice, suggesting that these systems promote manganese acquisition during infection. During the course of these studies, we observed that metal content and the importance of calprotectin varies between murine organs, and infection leads to profound changes in the anatomical distribution of manganese and zinc. In total, these studies provide insight into the mechanisms utilized by bacteria to evade host-imposed nutrient metal starvation and the critical importance of restricting manganese availability during infection. Staphylococcus aureus is a commensal organism that asymptomatically colonizes nearly one-third of the population (1). However, once S. aureus breaches the epithelial barrier, the bacterium is capable of infecting nearly every organ despite the robust defenses elaborated by the host (2). This adaptability contributes to the significant morbidity and mortality associated with S. aureus infections. The emergence of methicillin-and vancomycin-resistant isolates has compounded the threat of this organism, highlighting the need to identify new therapeutics (3-7). This is of particular importance, as antibiotic resistance is prevalent in both hospital-and community-acquired isolates (4,6,8).Metals are essential for all forms of life due to their critical contributions to protein structure and enzymatic function (9-12). To combat invading pathogens, vertebrates leverage the essentiality of transition metals by restricting their availability, a process termed "nutritional immunity" (10, 13). While the most prominent example of nutritional immunity is the restriction of iron (Fe) by the host, it has recently been discovered that vertebrates also limit manganese (Mn) and zinc (Zn) availability during infection (10,(13)(14)(15)(16)(17). In fact, examination of abscesses formed during S. aureus infection has revealed that these lesions are Mn and Zn depleted (14). It was subsequently determined that the Mnand Zn-binding S100 protein calprotectin (CP) is a critical component of this nutrient-withholding response (10,14,18,19). CPdeficient mice...

show abstract

Section: Figmentioning

confidence: 99%

MntABC and MntH Contribute to Systemic Staphylococcus aureus Infection by Competing with Calprotectin for Nutrient Manganese

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…4). In addition to this oxidative burst, a rising concept in host defense is ''nutritional immunity,'' a phrase recently coined by Eric Skaar to describe the molecular starvation of pathogens for the vital metal ions iron, zinc, and manganese (13,42). In the case of manganese, the metal is depleted from the macrophage phagolysosomes via the Nramp1 divalent metal transporter, and is also removed at the site of an infected abscess through neutrophil production of calprotectin, a metal chelating molecule (13,16,31,33,41).…”

Section: Mn Antioxidants In Multicellular Organisms and In Pathogenesismentioning

confidence: 99%

Manganese Complexes: Diverse Metabolic Routes to Oxidative Stress Resistance in Prokaryotes and Yeast

Culotta

Daly

2013

Antioxidants & Redox Signaling

135

118

View full text Add to dashboard Cite

Significance: Antioxidant enzymes are thought to provide critical protection to cells against reactive oxygen species (ROS). However, many organisms can fully compensate for the loss of such enzymatic defenses by accumulating metabolites and Mn 2+, which can form catalytic Mn-antioxidants. Accumulated metabolites can direct reactivity of Mn 2+ with superoxide and specifically shield proteins from oxidative damage. Recent Advances: There is mounting evidence that Mn-Pi (orthophosphate) complexes act as potent scavengers of superoxide in all three branches of life. Moreover, it is evident that Mn 2+ in complexes with carbonates, peptides, nucleosides, and organic acids can also form catalytic Mn-antioxidants, pointing to diverse metabolic routes to oxidative stress resistance. Critical Issues: What conditions favor utility of Mn-metabolites versus enzymatic means for removing ROS? Mn 2+ -metabolite defenses are critical for preserving the activity of repair enzymes in Deinococcus radiodurans exposed to intense radiation stress, and in Lactobacillus plantarum, which lacks antioxidant enzymes. In other microorganisms, Mn-antioxidants can serve as an auxiliary protection when enzymatic antioxidants are insufficient or fail. These findings of a critical role of Mn-antioxidants in the survival of prokaryotes under oxidative stress parallel the trends developing for the simple eukaryote Saccharomyces cerevisiae. Future Directions: Phosphates, peptides and organic acids are just a snapshot of the types of anionic metabolites that promote such reactivity of Mn 2+. Their probable roles in pathogen defense against the host immune response and in ROS-mediated signaling pathways are also areas that are worthy of serious investigation. Moreover, it is clear that these protective chemical processes can be harnessed for practical purposes. Antioxid. Redox Signal. 19,[933][934][935][936][937][938][939][940][941][942][943][944]

show abstract

“…Moreover, the ability of B. burgdorferi to accumulate high manganese may represent yet another fascinating adaptation of the organism to the metal starvation response of innate immunity. When infected, the host not only systemically starves pathogens of iron (16,17), but macrophages and neu- trophils attempt to limit manganese bioavailability for the invading species (43)(44)(45). High manganese is essential for virulence in B. burgdorferi (21), and SodA may only be part of the story.…”

Section: Discussionmentioning

confidence: 99%

A Manganese-rich Environment Supports Superoxide Dismutase Activity in a Lyme Disease Pathogen, Borrelia burgdorferi

Aguirre

Clark

McIlvin

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: SodA is an important virulence factor in Borrelia burgdorferi. Results: This SodA requires extraordinarily high intracellular manganese for activity and accumulates as either manganese or apoprotein, but not iron-bound. Conclusion: B. burgdorferiSodA is a unique Mn-SOD based on metal requirements and predicted structure. Significance: B. burgdorferi pathogenicity may be controlled by exploiting the unusual properties of SodA.

show abstract

Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity

Cited by 121 publications

References 233 publications

MntABC and MntH Contribute to Systemic Staphylococcus aureus Infection by Competing with Calprotectin for Nutrient Manganese

MntABC and MntH Contribute to Systemic Staphylococcus aureus Infection by Competing with Calprotectin for Nutrient Manganese

Manganese Complexes: Diverse Metabolic Routes to Oxidative Stress Resistance in Prokaryotes and Yeast

A Manganese-rich Environment Supports Superoxide Dismutase Activity in a Lyme Disease Pathogen, Borrelia burgdorferi

Contact Info

Product

Resources

About