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The pore forming alpha-toxin (hemolysin A, Hla) of Staphylococcus aureus (S. aureus) is a major virulence factor with relevance for the pathogenicity of this bacterium, which is involved in many cases of pneumonia and sepsis in humans. Until now, the presence of Hla in the body fluids of potentially infected humans could only be shown indirectly, e.g., by the presence of antibodies against Hla in serum samples or by hemolysis testing on blood agar plates of bacterial culture supernatants of the clinical isolates. In addition, nothing was known about the concentrations of Hla actually reached in the body fluids of the infected hosts. Western blot analyses on 36 samples of deep tracheal aspirates (DTA) isolated from 22 hospitalized sepsis patients using primary antibodies against different epitopes of the Hla molecule resulted in the identification of six samples from five patients containing monomeric Hla (approx. 33 kDa). Two of these samples showed also signals at the molecular mass of heptameric Hla (232 kDa). Semiquantitative analyses of the samples revealed that the concentrations of monomeric Hla ranged from 16 to 3200 ng/mL. This is, to our knowledge, the first study directly showing the presence of S. aureus Hla in samples of airway surface liquid in human patients.
Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.