SummaryStaphylococcus aureus infections can result in sepsis and septic shock associated with vascular damage and multiple organ failure. Apoptosis appears to play a key role during sepsis, and the ability of S. aureus to induce apoptosis in endothelial cells might contribute to metastatic infection. In contrast to leukocytes, in human umbilical vein endothelial cells and two endothelial cell lines neither purified a a a a -toxin nor staphylococcal supernatants were sufficient to induce apoptosis. Apoptosis induction instead required staphylococcal invasion as well as signals from metabolically active intracellular staphylococci. Only strongly haemolytic and invasive staphylococci, but not non-invasive strains induced apoptosis that was caspase-dependent but Fas-independent. However, only a subgroup of clinical isolates with an invasive and haemolytic phenotype induced apoptosis. Expression of a a a a -toxin in a non-haemolytic strain partially restored apoptosis induction, suggesting a role of a a a a -toxin as a trigger of apoptosis. Furthermore, infection of endothelial cells with isogenic mutants of various regulator genes revealed that apoptosis induction was dependent on the global regulator agr and the alternative sigma factor sigB , but not influenced by sarA . Together, our results indicate that the ability of S. aureus to induce apoptosis in endothelial cells is determined by multiple virulence factors.
SummaryStaphylococcus 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, a a a a -toxin is the major mediator of caspase activation and apoptosis. Here, we investigated the mechanisms of cell death induced by a a a a -toxin in peripheral blood mononuclear cells (MNC). We show that a a a a -toxin is required and sufficient for S. aureus -induced cell death not only in transformed Jurkat T cells but also in MNC. Low a a a atoxin doses (3-30 ng ml) dose-and timedependently induced apoptosis in both cell types, which was completely blocked by the caspase inhibitor zVAD-fmk. In Jurkat T cells and MNC, a a a a -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)-a a a a upon a a a a -toxin stimulation. Blocking endogenous TNF-a a a a with a TNF-a a a a 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-a a a a and a death receptor-dependent pathway are also involved, which may contribute to depletion of immune cells during S. aureus infection.
Bacterial peritonitis remains a serious complication of peritoneal dialysis. Although Staphylococcus epidermidis is the most common pathogen involved, infections with Staphylococcus aureus lead to severe peritoneal damage and are often associated with a dramatic loss of mesothelial cells. Induction of cell death appears to be involved in peritoneal damage and mesothelial cell loss during bacterial infections. Using cultured human peritoneal mesothelial cells (HMCs), we investigated the ability of different S. epidermidis and S. aureus strains to damage the HMC monolayer and to trigger cell death. We show that only a subgroup of live S. aureus isolates, characterized by an invasive and alpha-hemolysin-producing phenotype, induces cell death. None of the tested S. epidermidis strains, which were not invasive or hemolytic, had a cytotoxic effect. After host cell invasion, S. aureus resided within phagocytic vacuoles, and HMCs were apparently able to degrade staphylococci. However, even after prolonged infection, a high percentage of S. aureus remained alive within HMCs and might be released after host cell death. Cell death induced by S. aureus was accompanied by apoptotic alterations, such as DNA fragmentation, but was independent of endogenous FasL and tumor necrosis factor-alpha death ligand expression. Moreover, caspases were not involved in S. aureus-induced mesothelial cell death. In conclusion, our data indicate that mesothelial cell death might represent a major mechanism of S. aureus-induced damage of the peritoneum during bacterial peritonitis.
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