Bacterial Killing in Macrophages and Amoeba: Do they all use a Brass Dagger?

German, Nadezhda; Doyscher, Dominik; Rensing, Christopher

doi:10.2217/fmb.13.100

Cited by 68 publications

(60 citation statements)

References 73 publications

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“…This has led to the intriguing concept of the "brass dagger" in innate immunity (30), which then raises the question of how such a bactericidal mechanism could be integrated into the complex immune system of mammals. However, we suggest that the mechanisms behind the antibacterial actions of Cu and Zn may be more complicated than the simplistic view proposed by this model.…”

Section: Resultsmentioning

confidence: 99%

The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens

Djoko¹,

Ong²,

Walker

et al. 2015

Journal of Biological Chemistry

320

268

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Zinc (Zn) and copper (Cu) are essential for optimal innate immune function, and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilizes Cu and/or Zn intoxication to reduce the intracellular survival of pathogens. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function.Six first row d-block metal ions, manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), and zinc (Zn), are essential micronutrients in living organisms. Investigations and discussions of the roles of these trace metals in biology often relate to their acquisition, storage, and incorporation into enzymes. However, conditions where these metal ions are present in excess or are found in the wrong location, resulting in toxicity, have also been described. Thus, there are also systems that sequester, export, and detoxify excess trace metal ions. Today, the concept of trace metal homeostasis, in which various cellular actions maintain the fine balance between nutrition and toxicity, is well developed.Recently, the concept of "nutritional immunity" has emerged in the context of host defense against pathogens. This envisages a role for mechanisms that protect the host from invading pathogens by restricting their ability to acquire key transition metal ions. One example involves lipocalin, which binds siderophores and thereby prevents Fe acquisition by bacterial pathogens (1). Another is calprotectin, which restricts acquisition of Zn or Mn (2). However, what if the host was able to harness the toxic properties of transition metal ions and use them as bactericides? This review explores the evidence for an antimicrobial role for Cu and Zn in the host defense against bacterial pathogens.

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Section: Resultsmentioning

confidence: 99%

The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens

Djoko¹,

Ong²,

Walker

et al. 2015

Journal of Biological Chemistry

320

268

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“…Copper is also toxic to prokaryotes and eukaryotes at higher cellular concentrations (Gaetke & Chow, 2003), and copper (and zinc) involvement in phagosomal killing of bacteria engulfed by macrophages is now recognized as an important defence mechanism (German et al, 2013).…”

Section: Coppermentioning

confidence: 99%

“…According to the Irving-Williams series, copper has a higher affinity than other first-row transition metals for ligands, and displacement of iron from iron-sulphur clusters by copper in liquid culture experiments has been reported to be an important mechanism of copper toxicity (Macomber & Imlay, 2009). There is also a role for copper and ROS in phagosome killing of bacteria (reviewed by German et al, 2013).…”

Section: Coppermentioning

confidence: 99%

“…This has also found in farmed chickens and calves, and is linked to macrolide and glycopeptide resistance (Hasman & Aarestrup, 2002 There are several excellent and comprehensive review articles on copper resistance, which describe the genetics and biochemistry of resistance and the role of copper resistance in pathogenicity in great detail (e.g. Osman & Cavet, 2008;Solioz et al, 2010;Dupont et al, 2011;German et al, 2013;Chaturvedi & Henderson, 2014).…”

Section: Bacterial Antimicrobial Metal Ion Resistancementioning

confidence: 99%

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Bacterial antimicrobial metal ion resistance

Hobman

Crossman

2015

Journal of Medical Microbiology

304

217

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Metals such as mercury, arsenic, copper and silver have been used in various forms as antimicrobials for thousands of years with until recently, little understanding of their mode of action. The discovery of antibiotics and new organic antimicrobial compounds during the twentieth century saw a general decline in the clinical use of antimicrobial metal compounds, with the exception of the rediscovery of the use of silver for burns treatments and niche uses for other metal compounds. Antibiotics and new antimicrobials were regarded as being safer for the patient and more effective than the metal-based compounds they supplanted. Bacterial metal ion resistances were first discovered in the second half of the twentieth century. The detailed mechanisms of resistance have now been characterized in a wide range of bacteria. As the use of antimicrobial metals is limited, it is legitimate to ask: are antimicrobial metal resistances in pathogenic and commensal bacteria important now? This review details the new, rediscovered and 'never went away' uses of antimicrobial metals; examines the prevalence and linkage of antimicrobial metal resistance genes to other antimicrobial resistance genes; and examines the evidence for horizontal transfer of these genes between bacteria. Finally, we discuss the possible implications of the widespread dissemination of these resistances on re-emergent uses of antimicrobial metals and how this could impact upon the antibiotic resistance problem. IntroductionMetals and metalloids have a long empirical history of human usage in medicine and agriculture (as reviewed below), despite problems of host toxicity or doubts about their efficacy. Even now, a few toxic metal(loid) compounds are still first-line drugs or preferred-choice chemotherapeutics or antimicrobials, although the use of most of the previously popular antimicrobial metal(loid)s, such as mercury and arsenic/antimony compounds, has been reduced or phased out in the past 50 or so years. Other metals, such as silver and copper, still have limited uses in agriculture and medicine, but are also increasingly being included in consumer products, from clothing to computer keyboards, and are being promoted as useful additions to our arsenal of antimicrobials. Against this background of their current usage, it is reasonable to ask: what is the relevance of antimicrobial metals and bacterial resistances to them to medical microbiology in the twentyfirst century?Any attempt to address this question must be set against the backdrop of widely known problems and opportunities. We are faced with new and emerging opportunistic nosocomial and community-acquired pathogens; and increasing epidemic and pandemic multidrug-resistant (MDR) pathogens. There is a recognition that the antibiotic discovery pipeline has not delivered significant quantities of new antibiotics in the past few decades, and new formulations and uses for antimicrobial metals as weapons in the antimicrobial armoury are being proposed (Department of Health, 2013;Lemire et al., 2013). ...

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“…Our hypothesis is supported by the presence of the homologous copper transporter 1 (Ctr1) in macrophages and P80 in Dictyostelium discoideum and Acanthamoeba castellanii-proteins, both of which are involved in Cu + uptake upon phagocytosis. In addition, amoebae are known to contain P-type ATPases (German et al 2013;Burlando et al 2002), and similar to macrophages, at least one of these P-type ATPases in A. castellanii could be pumping Zn 2+ or Cu + into the phagosome of amoeba (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Survival in amoeba—a major selection pressure on the presence of bacterial copper and zinc resistance determinants? Identification of a “copper pathogenicity island”

Hao

Lüthje

Qin

et al. 2015

Appl Microbiol Biotechnol

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The presence of metal resistance determinants in bacteria usually is attributed to geological or anthropogenic metal contamination in different environments or associated with the use of antimicrobial metals in human healthcare or in agriculture. While this is certainly true, we hypothesize that protozoan predation and macrophage killing are also responsible for selection of copper/zinc resistance genes in bacteria. In this review, we outline evidence supporting this hypothesis, as well as highlight the correlation between metal resistance and pathogenicity in bacteria. In addition, we introduce and characterize the Bcopper pathogenicity island^identified in Escherichia coli and Salmonella strains isolated from copper-and zinc-fed Danish pigs.

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Bacterial Killing in Macrophages and Amoeba: Do they all use a Brass Dagger?

Cited by 68 publications

References 73 publications

The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens

The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens

Bacterial antimicrobial metal ion resistance

Survival in amoeba—a major selection pressure on the presence of bacterial copper and zinc resistance determinants? Identification of a “copper pathogenicity island”

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