title: alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling.
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.
authors.affiliation: Department of Immunology and Cell Biology, University of Münster, 48149 Münster, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bantel
authors.forename: B
authors.initials: B
authors.lastname: Sinha
authors.forename: W
authors.initials: W
authors.lastname: Domschke
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.forename: K
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: R U
authors.initials: RU
authors.lastname: Jänicke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003470:Culture Media; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000382:microbiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000382:microbiology; D010738:Type C Phospholipases / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003470:Culture Media; D003574:Cytochrome c Group; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D010738:Type C Phospholipases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases