P2X, P2X, and P2X Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing .

α-haemolysin (HlyA)-producing commonly inflict severe urinary tract infections, including pyelonephritis, which comprises substantial risk for sepsis. , the cytolytic effect of HlyA is mainly mediated by ATP release through the HlyA pore and subsequent P2X/P2X 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 that [Formula: see text] and [Formula: see text] mice are exceedingly sensitive to sepsis with uropathogenic . These mice have markedly lower survival, higher cytokine levels and activated intravascular coagulation. Quite the reverse is seen in [Formula: see text] mice, which had markedly lower cytokine levels and less coagulation activation compared to controls after exposure to uropathogenic . The high cytokine levels in the [Formula: see text] mouse are unexpected, since P2X is implicated in caspase-1-dependent IL-1β production. Here, we demonstrate that IL-1β production during sepsis with uropathogenic 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 and P2X receptor activation has a protective effect during severe infection.