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α-haemolysin (HlyA)-producing  Escherichia coli  commonly inflict severe urinary tract infections, including pyelonephritis, which comprises substantial risk for sepsis.  In vitro , the cytolytic effect of HlyA is mainly mediated by ATP release through the HlyA pore and subsequent P2X 1 /P2X 7  receptor activation. This amplification of the lytic process is not unique to HlyA but is observed by many other pore-forming proteins including complement-induced haemolysis. Since free hemoglobin in the blood is known to be associated with a worse outcome in sepsis one could speculate that inhibition of P2X receptors would ameliorate the course of sepsis. Surprisingly, this study demonstrates thatP  2  X    1    −  /  −andP  2  X    4    −  /  −mice are exceedingly sensitive to sepsis with uropathogenic  E. coli . These mice have markedly lower survival, higher cytokine levels and activated intravascular coagulation. Quite the reverse is seen inP  2  X    1    −  /  −mice, which had markedly lower cytokine levels and less coagulation activation compared to controls after exposure to uropathogenic  E. coli . The high cytokine levels in theP  2  X    7    −  /  −mouse are unexpected, since P2X 7  is implicated in caspase-1-dependent IL-1β production. Here, we demonstrate that IL-1β production during sepsis with uropathogenic  E. coli  is mediated by caspase-8, since caspase-8 and RIPK3 double knock out mice show substantially lower cytokine during sepsis and increased survival after injection of TNFα. These data support that P2X 7  and P2X 4  receptor activation has a protective effect during severe  E. coli  infection.

P2X1, P2X4, and P2X7 Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing Escherichia coli