Updated project metadata. Alpha-toxin is a major virulence factor of Staphylococcus aureus and plays an important role in S. aureus-induced pneumonia. Different sensitivities toward the toxin of various host cell types have been observed. In this study we investigated internalization of pore-containing areas of the plasma membrane in these cell types as well as potential pathways for heptamer degradation (lysosomal, proteasomal) or disposal (formation of exosomes/microvesicles containing toxin pores). Comparisons of heptamer degradation rates under inhibition of lysosomal or proteasomal degradation revealed that an important route of heptamer degradation at least in S9 cells seemed to be the lysosomal pathway while proteasomal degradation did not seem to be relevant. Exosomes prepared from culture supernatants of toxin-exposed S9 cells, contained alpha-toxin as well as low amounts of marker proteins of exosomes and microvesicles. These results indicate that the ability of lysosomal degradation of internalized toxin heptamers may be the most important determinant of toxin-resistance of some types of airway epithelial cells. In this study, we compared the proteomes of rHla treated (90 min), 8 h starvation and, 48 h starvation for the S9 cells by mass spectrometry.