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Published online 5 November 2001. doi:10.1083/jcb.200105081
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© The Rockefeller University Press, 0021-9525/2001/11/637 $5.00
The Journal of Cell Biology, Volume 155, Number 4, November 12, 2001 637-648

Article

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

Heike Bantel1,2, Bhanu Sinha3, Wolfram Domschke2, Georg Peters3, Klaus Schulze-Osthoff1 and Reiner U. Jänicke1

1 Department of Immunology and Cell Biology, University of Münster, 48149 Münster, Germany
2 Department of Internal Medicine B, University of Münster, 48149 Münster, Germany
3 Institute of Medical Microbiology, University of Münster, 48149 Münster, Germany

Address correspondence to Reiner U. Jänicke, Dept. of Immunology and Cell Biology, University of Münster, Röntgenstrasse 21, 48149 Münster, Germany. Tel.: 49-251-83-52948. Fax: 49-251-83-52250. E-mail: r.janicke{at}uni-muenster.de

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.

Key Words: S. aureus; {alpha}-toxin; apoptosis; caspases; mitochondria


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