α-Hemolysin fromEscherichia coliuses endogenous amplification through P2X receptor activation to induce hemolysis

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Abstract
Escherichia coliis the dominant facultative bacterium in the normal intestinal flora.E. coliis, however, also responsible for the majority of serious extraintestinal infections. There are distinct serotypical differences between facultative and invasiveE. colistrains. Invasive strains frequently produce virulence factors such as α-hemolysin (HlyA), which causes hemolysis by forming pores in the erythrocyte membrane. The present study reveals that this pore formation triggers purinergic receptor activation to mediate the full hemolytic action. Non-selective ATP-receptor (P2) antagonists (PPADS, suramin) and ATP scavengers (apyrase, hexokinase) concentration dependently inhibited HlyA-induced lysis of equine, murine, and human erythrocytes. The pattern of responsiveness to more selective P2-antagonists implies that both P2X1and P2X7receptors are involved in HlyA-induced hemolysis in all three species. In addition, our results also propose a role for the pore protein pannexin1 in HlyA-induced hemolysis, as non-selective inhibitors of this channel significantly reduced hemolysis in the three species. In conclusion, activation of P2X receptors and possibly also pannexins augment hemolysis induced by the bacterial toxin, HlyA. These findings potentially have clinical perspectives as P2 antagonists may ameliorate symptoms during sepsis with hemolytic bacteria.