P2Y2 receptors are essential for hepatic clearance of uropathogenic E. coli in a murine sepsis model

Urosepsis is a life-threatening condition most frequently caused by E. coli expressing important virulence factors, including α-haemolysin (HlyA). The pore-forming exotoxin HlyA releases ATP upon its insertion into cellular membranes, and the majority of the biological effects of HlyA are mediated through ATP-dependent P2-receptor activation, including the HlyA-mediated thrombocyte activation. We have recently shown that uropathogenic E. coli (UPEC) bind to thrombocytes immediately after entering the blood, and the following hepatic clearance leads to early thrombocytopenia during bacteraemia. Here, we demonstrate that P2Y ₂ -deficient mice had markedly shorter survival (LD ₅₀ of 185 minutes) compared to wildtype (340 minutes), a response paralleled in mice infused with the P2Y ₂ receptor antagonist AR-C118925XX. The P2Y ₂ ^-/- mice exhibited a blunted sepsis-induced thrombocytopenia compared to wildtype and sepsis-induced reduction in mature neutrophils in the blood. Strikingly, the P2Y ₂ -deficient mice had inadequate hepatic clearance of UPEC, resulting in the accumulation of bacteria in the lungs, while thrombocytes were mainly sequestered in the kidneys. Hence, it is likely that the insufficient hepatic elimination of UPEC is responsible for the reduced survival in the P2Y ₂ ^-/- mice. Taken together, we show that the lack of functional P2Y ₂ receptors is essential for fast and proper hepatic clearance of UPEC and the survival time during urosepsis. Moreover, the data support the notion that an early reduction in circulating thrombocytes is important for a relevant host response to acute bacteraemia.