N-Terminal ArgD Peptides from the Classical Staphylococcus aureus Agr System Have Cytotoxic and Proinflammatory Activities

Gonzalez, David J.; Corriden, Ross; Akong-Moore, Kathryn; Olson, Joshua; Dorrestein, Pieter C.; Nizet, Victor

doi:10.1016/j.chembiol.2014.09.015

Cited by 19 publications

(16 citation statements)

References 28 publications

(32 reference statements)

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“…So far, different bacterial factors that are released by viable bacteria have been described to trigger the formation of NETs in response to S. aureus infections: the N-terminal ArgD peptides (49), leukotoxin GH (47), and Panton–Valentin leukocidin (PVL) (48). Importantly, those exotoxins trigger formation of NETs by completely different mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Formation of Neutrophil Extracellular Traps under Low Oxygen Level

et al. 2016

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Since their discovery, neutrophil extracellular traps (NETs) have been characterized as a fundamental host innate immune defense mechanism. Conversely, excessive NET-release may have a variety of detrimental consequences for the host. A fine balance between NET formation and elimination is necessary to sustain a protective effect during an infectious challenge. Our own recently published data revealed that stabilization of hypoxia-inducible factor 1α (HIF-1α) by the iron chelating HIF-1α-agonist desferoxamine or AKB-4924 enhanced the release of phagocyte extracellular traps. Since HIF-1α is a global regulator of the cellular response to low oxygen, we hypothesized that NET formation may be similarly increased under low oxygen conditions. Hypoxia occurs in tissues during infection or inflammation, mostly due to overconsumption of oxygen by pathogens and recruited immune cells. Therefore, experiments were performed to characterize the formation of NETs under hypoxic oxygen conditions compared to normoxia. Human blood-derived neutrophils were isolated and incubated under normoxic (21%) oxygen level and compared to hypoxic (1%) conditions. Dissolved oxygen levels were monitored in the primary cell culture using a Fibox4-PSt3 measurement system. The formation of NETs was quantified by fluorescence microscopy in response to the known NET-inducer phorbol 12-myristate 13-acetate (PMA) or Staphylococcus (S.) aureus wild-type and a nuclease-deficient mutant. In contrast to our hypothesis, spontaneous NET formation of neutrophils incubated under hypoxia was distinctly reduced compared to control neutrophils incubated under normoxia. Furthermore, neutrophils incubated under hypoxia showed significantly reduced formation of NETs in response to PMA. Gene expression analysis revealed that mRNA level of hif-1α as well as hif-1α target genes was not altered. However, in good correlation to the decreased NET formation under hypoxia, the cholesterol content of the neutrophils was significantly increased under hypoxia. Interestingly, NET formation in response to viable S. aureus wild-type or nuclease-deficient strain was retained under hypoxia. Our results lead to the conclusion that hypoxia is not the ideal tool to analyze HIF-1α in neutrophils. However, the data clearly suggest that neutrophils react differently under hypoxia compared to normoxia and thereby highlight the importance of the usage of physiological relevant oxygen level when studying neutrophil functions.

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Section: Resultsmentioning

confidence: 99%

Formation of Neutrophil Extracellular Traps under Low Oxygen Level

et al. 2016

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“…It should be noted that only indirect evidence is provided in this study for the ability of SpsB to cleave the native thiolactone intermediate. More recently, large quantities of the AgrD leader peptide have been detected in the S. aureus extracellular matrix (Gonzalez et al, 2014; Schwartz et al, 2014). This result also supports the translocation-first model, as the alternative, proteolysis-first model would entail separate translocation of both leader and AIP fragments, which would be substantially less economical.…”

Section: Biochemistry Of Agr Autoinductionmentioning

confidence: 99%

Regulation of Virulence in Staphylococcus aureus : Molecular Mechanisms and Remaining Puzzles

Wang

Muir

2016

Cell Chemical Biology

171

201

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Summary The agr locus encodes a quorum sensing (QS) circuit required for the virulence of a spectrum of gram-positive pathogens and is, therefore, regarded as an important target for the development of chemotherapeutics. In recent years, many of the biochemical events in the Staphylococcus aureus agr circuit have been reconstituted and subject to quantitative analysis in vitro. This work, in conjunction with structural studies on several key players in the signaling circuit, has furnished mechanistic insights into the regulation and evolution of the agr quorum sensing system. Herein, we review this progress and discuss the remaining open questions in the area. We also highlight advances in the discovery of small-molecule agr modulators and how the newly available biochemical and structural information might be leveraged for the design of next generation therapeutics targeting the agr system.

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“…In the case of the leading human pathogen S. aureus , three different exotoxins enhance the release of NETs: N-terminal AgrD peptides ( Gonzalez et al, 2014 ), leukotoxin GH ( Malachowa et al, 2013 ), also known as LukAB ( Dumont et al, 2011 ), thus named here LukGH/AB, and Panton-Valentin leukocidin (PVL; Pilsczek et al, 2010 ). AgrD is the precursor for the auto-inducing peptide in a well-known quorum sensing system regulating virulence phenotypes of S. aureus .…”

Section: Bacterial Exotoxins That Modulate Net Formationmentioning

confidence: 99%

Interaction of Bacterial Exotoxins with Neutrophil Extracellular Traps: Impact for the Infected Host

Köckritz-Blickwede

Blodkamp²,

Nizet

2016

Front. Microbiol.

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Since their discovery in 2004, neutrophil extracellular traps (NETs) have been characterized as a fundamental host innate immune defense against various pathogens. Released in response to infectious and pro-inflammatory stimuli, NETs can immobilize invading pathogens within a fibrous matrix consisting of DNA, histones, and antimicrobial peptides. Conversely, excessive or dysregulated NET release may hold a variety of detrimental consequences for the host. A fine balance between NET formation and elimination is necessary to sustain a protective effect during infectious challenge. In recent years, a number of microbial virulence factors have been shown to modulate formation of NETs, thereby facilitating colonization or spread within the host. In this mini-review we summarize the contemporary research on the interaction of bacterial exotoxins with neutrophils that modulate NET production, focusing particular attention on consequences for the host. Understanding host–pathogen dynamics in this extracellular battlefield of innate immunity may provide novel therapeutic approaches for infectious and inflammatory disorders.

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N-Terminal ArgD Peptides from the Classical Staphylococcus aureus Agr System Have Cytotoxic and Proinflammatory Activities

Cited by 19 publications

References 28 publications

Formation of Neutrophil Extracellular Traps under Low Oxygen Level

Formation of Neutrophil Extracellular Traps under Low Oxygen Level

Regulation of Virulence in Staphylococcus aureus : Molecular Mechanisms and Remaining Puzzles

Interaction of Bacterial Exotoxins with Neutrophil Extracellular Traps: Impact for the Infected Host

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