title: Staphylococcus aureus alpha-toxin induces apoptosis in peripheral blood mononuclear cells: role of endogenous tumour necrosis factor-alpha and the mitochondrial death pathway.
abstract: Staphylococcus aureus infections can result in septic and toxic shock with depletion of immune cells and massive cytokine production. Recently, we showed that, in S. aureus-infected Jurkat T cells, alpha-toxin is the major mediator of caspase activation and apoptosis. Here, we investigated the mechanisms of cell death induced by alpha-toxin in peripheral blood mononuclear cells (MNC). We show that alpha-toxin is required and sufficient for S. aureus-induced cell death not only in transformed Jurkat T cells but also in MNC. Low alpha-toxin doses (3-30 ng ml-1) dose- and time-dependently induced apoptosis in both cell types, which was completely blocked by the caspase inhibitor zVAD-fmk. In Jurkat T cells and MNC, alpha-toxin induced the breakdown of the mitochondrial membrane potential and the intrinsic activation of caspase-3, -8 and -9. Interestingly, unlike in Jurkat T cells, apoptosis in MNC was additionally mediated by a caspase-9-independent component. MNC, but not Jurkat T cells, produced tumour necrosis factor (TNF)-alpha upon alpha-toxin stimulation. Blocking endogenous TNF-alpha with a TNF-alpha receptor antagonist partially decreased apoptosis in MNC. Our data therefore suggest that, whereas in Jurkat T cells apoptosis is solely mediated by the mitochondrial pathway, in MNC endogenous TNF-alpha and a death receptor-dependent pathway are also involved, which may contribute to depletion of immune cells during S. aureus infection.
authors.affiliation: Institute of Medical Microbiology, Medical School of University Hospital of Münster, Domagkstrasse 10, D-48149 Münster, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Haslinger
authors.forename: Katrin
authors.initials: K
authors.lastname: Strangfeld
authors.forename: Georg
authors.initials: G
authors.lastname: Peters
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Bhanu
authors.initials: B
authors.lastname: Sinha
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D001427:Bacterial Toxins; D061945:Caspase Inhibitors; D006460:Hemolysin Proteins; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C021091:staphylococcal alpha-toxin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases