<i>Staphylococcus aureus</i>α-toxin-mediated cation entry depolarizes membrane potential and activates p38 MAP kinase in airway epithelial cells

Eiffler, Ina; Behnke, Jane; Ziesemer, Sabine; Müller, Christian; Hildebrandt, Jan‐Peter

doi:10.1152/ajplung.00090.2016

Cited by 24 publications

(35 citation statements)

References 63 publications

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“…Experiments with HlgCB indicated that ion flux did not occur through toxin pores, but occurred indirectly through Na + /K + ATPases [152]. In Hla treated lung epithelial cells, K + efflux is sufficient to induce p38-MAPK signaling [153]. Similarly, K + efflux was responsible for initiating inflammasome activation in monocytes following LukAB intoxication [92].…”

Section: Cellular Effects Of Toxin Actionmentioning

confidence: 99%

“…Similarly, K + efflux was responsible for initiating inflammasome activation in monocytes following LukAB intoxication [92]. Other signaling pathways that are initiated by Hla-pore formation include the p38, Erk, and c-Fos signaling pathways, which are associated with inflammatory or immune signaling, as well as the initiation of cell survival pathways [153, 154]. In particular, the p38 pathway has been shown to be activated in cells treated with Hla-concentrations that were insufficient to induce detectable levels of cell death, indicating the sensitivity of the pathway [116].…”

Section: Cellular Effects Of Toxin Actionmentioning

confidence: 99%

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Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Seilie

Wardenburg

2017

Seminars in Cell & Developmental Biology

170

136

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Staphylococcus aureus is a prominent human pathogen capable of infecting a variety of host species and tissue sites. This versatility stems from the pathogen’s ability to secrete diverse host-damaging virulence factors. Among these factors, the S. aureus pore-forming toxins (PFTs), α-toxin and the bicomponent leukocidins, have garnered much attention for their ability to lyse cells at low concentrations and modulate disease severity. Although many of these toxins were discovered nearly a century ago, their host cell specificity has only been elucidated over the past five to six years, starting with the discovery of the eukaryotic receptor for α-toxin and rapidly followed by identification of the leukocidin receptors. The identification of these receptors has revealed the species- and cell type-specificity of toxin binding, and provided insight into non-lytic effects of PFT intoxication that contribute to disease pathogenesis.

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Section: Cellular Effects Of Toxin Actionmentioning

confidence: 99%

Section: Cellular Effects Of Toxin Actionmentioning

confidence: 99%

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Seilie

Wardenburg

2017

Seminars in Cell & Developmental Biology

170

136

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“…Additionally, treatment of airway epithelial cells with recombinant α-hemolysin results in plasma membrane depolarization, and increased phosphorylation of paxillin and p38 MAP kinase, a signal transduction module involved in host defensive actions (Eiffler et al, 2016). Lastly, staphylococcal EsxA protein interferes with epithelial cell apoptotic pathways and, together with EsxB, mediates the release of intracellular staphylococci from the host cells (Truong-Bolduc et al, 2015).…”

Section: The Epithelial Surface As the First Line Of Defense Against mentioning

confidence: 99%

Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases

Pietrocola

Nobile

Rindi

et al. 2017

Front. Cell. Infect. Microbiol.

121

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Neutrophils, complement system and skin collectively represent the main elements of the innate immune system, the first line of defense of the host against many common microorganisms. Bacterial pathogens have evolved strategies to counteract all these defense activities. Specifically, Staphylococcus aureus, a major human pathogen, secretes a variety of immune evasion molecules including proteases, which cleave components of the innate immune system or disrupt the integrity of extracellular matrix and intercellular connections of tissues. Additionally, S. aureus secretes proteins that can activate host zymogens which, in turn, target specific defense components. Secreted proteins can also inhibit the anti-bacterial function of neutrophils or complement system proteases, potentiating S. aureus chances of survival. Here, we review the current understanding of these proteases and modulators of host proteases in the functioning of innate immunity and describe the importance of these mechanisms in the pathology of staphylococcal diseases.

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“…Treatment of cells with an rHla-variant (rHla-H35L), which is not able to form functional transmembrane pores [30], did not affect mitochondrial membrane potential. As exposure of airway epithelial cells to rHla results in calcium influx into the cytosol [31] and mitochondria are able to buffer cellular calcium loading by importing calcium ions into the mitochondrial matrix [32], we measured [Ca 2+ ] within the mitochondrial matrix using the fluorescent dye Rhod-2. As shown in Figure 2E, exposure of cells to 2000 ng/mL rHla resulted in an increase in [Ca 2+ ] m to approximately 250% of the initial value over a period of 40 min compared with the controls.…”

Section: Resultsmentioning

confidence: 99%

“…There are two possible explanations for this finding. The first is that rHla pore formation which has been shown to result in an influx of sodium and calcium ions into the cytosol, and plasma membrane depolarization [31] reduces mitochondrial inner membrane potential and mitochondrial ATP production. This would lower the cellular ATP content per se without any effects on extracellular ATP.…”

Section: Discussionmentioning

confidence: 99%

ATP Release from Human Airway Epithelial Cells Exposed to Staphylococcus aureus Alpha-Toxin

Baaske

Richter

Möller

et al. 2016

Toxins

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Airway epithelial cells reduce cytosolic ATP content in response to treatment with S. aureus alpha-toxin (hemolysin A, Hla). This study was undertaken to investigate whether this is due to attenuated ATP generation or to release of ATP from the cytosol and extracellular ATP degradation by ecto-enzymes. Exposure of cells to rHla did result in mitochondrial calcium uptake and a moderate decline in mitochondrial membrane potential, indicating that ATP regeneration may have been attenuated. In addition, ATP may have left the cells through transmembrane pores formed by the toxin or through endogenous release channels (e.g., pannexins) activated by cellular stress imposed on the cells by toxin exposure. Exposure of cells to an alpha-toxin mutant (H35L), which attaches to the host cell membrane but does not form transmembrane pores, did not induce ATP release from the cells. The Hla-mediated ATP-release was completely blocked by IB201, a cyclodextrin-inhibitor of the alpha-toxin pore, but was not at all affected by inhibitors of pannexin channels. These results indicate that, while exposure of cells to rHla may somewhat reduce ATP production and cellular ATP content, a portion of the remaining ATP is released to the extracellular space and degraded by ecto-enzymes. The release of ATP from the cells may occur directly through the transmembrane pores formed by alpha-toxin.

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Staphylococcus aureusα-toxin-mediated cation entry depolarizes membrane potential and activates p38 MAP kinase in airway epithelial cells

Abstract: Eiffler I, Behnke J, Ziesemer S, Müller C, Hildebrandt JP. Staphylococcus aureus ␣-toxin-mediated cation entry depolarizes membrane potential and activates p38 MAP kinase in airway epithelial cells.

Cited by 24 publications

References 63 publications

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases

ATP Release from Human Airway Epithelial Cells Exposed to Staphylococcus aureus Alpha-Toxin

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