Abstract
Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla-treatment including activation of the epidermal growth factor receptor EGFR and mitogen-activated protein kinases MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects.
Highlights
Alpha-toxin is a major pore-forming cytotoxin released by most Staphylococcus aureus strains and a key factor in the pathogenesis of S. aureus diseases, including pneumonia [1,2,3]
Corresponding to the cell type-specific changes in cell numbers, a Recombinant Hla (rHla)-induced drop in fitness was observed from 90% at 10 min to 50% at 24 h for 16HBE14o- cells, whereas S9 cells were much less affected by rHla over the same period of time
Staphylococcal pore-forming Hla has been detected in patients suffering S. aureus diseases [48, 49] and was identified as major virulence-associated factor, since vaccination against Hla protected animals from developing S. aureus-mediated pneumonia [1]
Summary
Alpha-toxin (or alpha-hemolysin, Hla) is a major pore-forming cytotoxin released by most Staphylococcus aureus strains and a key factor in the pathogenesis of S. aureus diseases, including pneumonia [1,2,3]. The interaction of Hla with susceptible host cells is characterized by attachment to the membrane, oligomerization to a heptameric structure followed by formation.
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