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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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Related in: MedlinePlus

S. aureus mediates cell death and caspase activation via the Bcl-2–controlled mitochondrial death pathway. Assessment of cell death (A and B) and caspase-3–like activity (D and E) in Jurkat vector control cells (□) or cells overexpressing Bcl-2 (▪). Cells were incubated with increasing concentrations of Wood 46 supernatant (A and D), RN6390 supernatant (B), or α-toxin (E). Assessment of etoposide- or CD95-induced apoptosis (C) and DEVDase activity (F) in vector cells (filled bars) and Bcl-2 cells (open bars) served as controls. Cell death and DEVDase activity were determined after 24 and 4 h, respectively.
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fig8: S. aureus mediates cell death and caspase activation via the Bcl-2–controlled mitochondrial death pathway. Assessment of cell death (A and B) and caspase-3–like activity (D and E) in Jurkat vector control cells (□) or cells overexpressing Bcl-2 (▪). Cells were incubated with increasing concentrations of Wood 46 supernatant (A and D), RN6390 supernatant (B), or α-toxin (E). Assessment of etoposide- or CD95-induced apoptosis (C) and DEVDase activity (F) in vector cells (filled bars) and Bcl-2 cells (open bars) served as controls. Cell death and DEVDase activity were determined after 24 and 4 h, respectively.

Mentions: Next, we examined the possibility that caspase activation by S. aureus is mediated via the intrinsic death pathway. For this purpose, Jurkat cells stably expressing the antiapoptotic protein Bcl-2 that is known to prevent mitochondrial cytochrome c release were incubated with increasing concentrations of Wood 46 (Fig. 8 A) or RN6390 (Fig. 8 B) supernatants. Cell death was inhibited dose dependently in Jurkat Bcl-2 cells compared with similarly treated Jurkat vector cells. However, cell death inhibition was observed only when low concentrations of S. aureus culture supernatants were used, whereas cell death induced with higher concentrations of Wood 46 or RN6390 supernatants was not affected by Bcl-2. This is consistent with our previous results, demonstrating that only low concentrations of S. aureus culture supernatants induce caspase activation (Figs. 3, 4, and 6).


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. aureus mediates cell death and caspase activation via the Bcl-2–controlled mitochondrial death pathway. Assessment of cell death (A and B) and caspase-3–like activity (D and E) in Jurkat vector control cells (□) or cells overexpressing Bcl-2 (▪). Cells were incubated with increasing concentrations of Wood 46 supernatant (A and D), RN6390 supernatant (B), or α-toxin (E). Assessment of etoposide- or CD95-induced apoptosis (C) and DEVDase activity (F) in vector cells (filled bars) and Bcl-2 cells (open bars) served as controls. Cell death and DEVDase activity were determined after 24 and 4 h, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: S. aureus mediates cell death and caspase activation via the Bcl-2–controlled mitochondrial death pathway. Assessment of cell death (A and B) and caspase-3–like activity (D and E) in Jurkat vector control cells (□) or cells overexpressing Bcl-2 (▪). Cells were incubated with increasing concentrations of Wood 46 supernatant (A and D), RN6390 supernatant (B), or α-toxin (E). Assessment of etoposide- or CD95-induced apoptosis (C) and DEVDase activity (F) in vector cells (filled bars) and Bcl-2 cells (open bars) served as controls. Cell death and DEVDase activity were determined after 24 and 4 h, respectively.
Mentions: Next, we examined the possibility that caspase activation by S. aureus is mediated via the intrinsic death pathway. For this purpose, Jurkat cells stably expressing the antiapoptotic protein Bcl-2 that is known to prevent mitochondrial cytochrome c release were incubated with increasing concentrations of Wood 46 (Fig. 8 A) or RN6390 (Fig. 8 B) supernatants. Cell death was inhibited dose dependently in Jurkat Bcl-2 cells compared with similarly treated Jurkat vector cells. However, cell death inhibition was observed only when low concentrations of S. aureus culture supernatants were used, whereas cell death induced with higher concentrations of Wood 46 or RN6390 supernatants was not affected by Bcl-2. This is consistent with our previous results, demonstrating that only low concentrations of S. aureus culture supernatants induce caspase activation (Figs. 3, 4, and 6).

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