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alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling.

Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K, Jänicke RU - J. Cell Biol. (2001)

Bottom Line: Furthermore, alpha-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2.Together with our finding that alpha-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus alpha-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors.Hence, our findings clearly define a signaling pathway used in S. aureus-induced cytotoxicity and may provide a molecular rationale for future therapeutic interventions in bacterial infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Cell Biology, University of Münster, 48149 Münster, Germany.

ABSTRACT
Infections with Staphylococcus aureus, a common inducer of septic and toxic shock, often result in tissue damage and death of various cell types. Although S. aureus was suggested to induce apoptosis, the underlying signal transduction pathways remained elusive. We show that caspase activation and DNA fragmentation were induced not only when Jurkat T cells were infected with intact bacteria, but also after treatment with supernatants of various S. aureus strains. We also demonstrate that S. aureus-induced cell death and caspase activation were mediated by alpha-toxin, a major cytotoxin of S. aureus, since both events were abrogated by two different anti-alpha-toxin antibodies and could not be induced with supernatants of an alpha-toxin-deficient S. aureus strain. Furthermore, alpha-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2. Together with our finding that alpha-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus alpha-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors. Hence, our findings clearly define a signaling pathway used in S. aureus-induced cytotoxicity and may provide a molecular rationale for future therapeutic interventions in bacterial infections.

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S. aureusα-toxin induces caspase-3 activation in human PBL and monocytes. DEVDase activity in extracts of PBL (A and B) and monocytes (C and D). Cells were either incubated for 4 h with the indicated α-toxin concentrations (A and C) or with 30 ng/ml α-toxin for the indicated times (B and D).
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fig5: S. aureusα-toxin induces caspase-3 activation in human PBL and monocytes. DEVDase activity in extracts of PBL (A and B) and monocytes (C and D). Cells were either incubated for 4 h with the indicated α-toxin concentrations (A and C) or with 30 ng/ml α-toxin for the indicated times (B and D).

Mentions: Infection with S. aureus is accompanied by the death of immune competent cells including T cells and monocytes (Weinrauch and Zychlinsky, 1999; Gao and Kwaik, 2000). To analyze the role of α-toxin in this respect and to establish a more general mechanism on various clinically relevant cell types, human PBLs and monocytes were incubated for the indicated times with various concentrations of the two α-toxin preparations. As shown in Fig. 5, caspase-3 was activated efficiently in PBL and monocytes by both α-toxin preparations in a time- and dose-dependent manner. Similar to the results obtained with Jurkat cells (Fig. 2 F; unpublished data), both α-toxin preparations induced activation of caspase-3 in PBL or monocytes with almost identical efficiencies, indicating that α-toxin might contribute to cell death observed after S. aureus infection.


alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling.

Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K, Jänicke RU - J. Cell Biol. (2001)

S. aureusα-toxin induces caspase-3 activation in human PBL and monocytes. DEVDase activity in extracts of PBL (A and B) and monocytes (C and D). Cells were either incubated for 4 h with the indicated α-toxin concentrations (A and C) or with 30 ng/ml α-toxin for the indicated times (B and D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198876&req=5

fig5: S. aureusα-toxin induces caspase-3 activation in human PBL and monocytes. DEVDase activity in extracts of PBL (A and B) and monocytes (C and D). Cells were either incubated for 4 h with the indicated α-toxin concentrations (A and C) or with 30 ng/ml α-toxin for the indicated times (B and D).
Mentions: Infection with S. aureus is accompanied by the death of immune competent cells including T cells and monocytes (Weinrauch and Zychlinsky, 1999; Gao and Kwaik, 2000). To analyze the role of α-toxin in this respect and to establish a more general mechanism on various clinically relevant cell types, human PBLs and monocytes were incubated for the indicated times with various concentrations of the two α-toxin preparations. As shown in Fig. 5, caspase-3 was activated efficiently in PBL and monocytes by both α-toxin preparations in a time- and dose-dependent manner. Similar to the results obtained with Jurkat cells (Fig. 2 F; unpublished data), both α-toxin preparations induced activation of caspase-3 in PBL or monocytes with almost identical efficiencies, indicating that α-toxin might contribute to cell death observed after S. aureus infection.

Bottom Line: Furthermore, alpha-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2.Together with our finding that alpha-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus alpha-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors.Hence, our findings clearly define a signaling pathway used in S. aureus-induced cytotoxicity and may provide a molecular rationale for future therapeutic interventions in bacterial infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Cell Biology, University of Münster, 48149 Münster, Germany.

ABSTRACT
Infections with Staphylococcus aureus, a common inducer of septic and toxic shock, often result in tissue damage and death of various cell types. Although S. aureus was suggested to induce apoptosis, the underlying signal transduction pathways remained elusive. We show that caspase activation and DNA fragmentation were induced not only when Jurkat T cells were infected with intact bacteria, but also after treatment with supernatants of various S. aureus strains. We also demonstrate that S. aureus-induced cell death and caspase activation were mediated by alpha-toxin, a major cytotoxin of S. aureus, since both events were abrogated by two different anti-alpha-toxin antibodies and could not be induced with supernatants of an alpha-toxin-deficient S. aureus strain. Furthermore, alpha-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2. Together with our finding that alpha-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus alpha-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors. Hence, our findings clearly define a signaling pathway used in S. aureus-induced cytotoxicity and may provide a molecular rationale for future therapeutic interventions in bacterial infections.

Show MeSH
Related in: MedlinePlus