Abstract
Epithelial cells act as an interface between human mucosal surfaces and the surrounding environment. As a result, they are responsible for the initiation of local immune responses, which may be crucial for prevention of invasive infection. Here we show that epithelial cells detect the presence of bacterial pore-forming toxins (including pneumolysin from Streptococcus pneumoniae, alpha-hemolysin from Staphylococcus aureus, streptolysin O from Streptococcus pyogenes, and anthrolysin O from Bacillus anthracis) at nanomolar concentrations, far below those required to cause cytolysis. Phosphorylation of p38 MAPK appears to be a conserved response of epithelial cells to subcytolytic concentrations of bacterial poreforming toxins, and this activity is inhibited by the addition of high molecular weight osmolytes to the extracellular medium. By sensing osmotic stress caused by the insertion of a sublethal number of pores into their membranes, epithelial cells may act as an early warning system to commence an immune response, while the local density of toxin-producing bacteria remains low. Osmosensing may thus represent a novel innate immune response to a common bacterial virulence strategy.
Highlights
Elaboration of pore-forming toxins (PFT)2 is a common theme in bacterial pathogenesis
PFT are secreted as monomers, which insert into host cell membranes, form homo-oligomers, and lead to the disruption of membrane integrity [1]
Most notably the major Gram-positive pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, PFT are essential for full virulence of the organism, their precise mechanisms of action in vivo are not well understood [3,4,5]
Summary
Elaboration of pore-forming toxins (PFT)2 is a common theme in bacterial pathogenesis. To confirm that PFT were sufficient as well as necessary for activation of epithelial p38 MAPK in response to Gram-positive bacteria, we stimulated epithelial cells with purified S. aureus ␣-hemolysin, Ply, or other members of the cholesterol-dependent cytolysin family, SLO and ALO (Fig. 2).
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