SUMMARY Sepsis is caused by severe infection, which results in systemic disease. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. One reason for this high morbidity and mortality is that the treatment of sepsis relies only on supportive therapy including antibiotics and fluids and there are no FDA- approved specific drugs to treat sepsis. Current concepts suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune system. This manifests as an inability to control bacterial growth and dissemination, and increased inflammation, processes that are interrelated and are due, in a large part, to macrophage dysfunction. ATP is a danger-associated molecular pattern, which is released from the intracellular into the extracellular space during infection, inflammation, and hypoxia, which are all present during sepsis. Detection of the released ATP by P2 purinergic receptors on the surface of immune cells, including macrophages, alerts the immune system to danger and initiates and orchestrates host immunity and inflammation. P2 receptors fall into two classes, the ionotropic P2X (P2X1-7) receptors, and the metabotropic P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors. ATP activation of P2X7 receptors has been implicated in killing of obligate intracellular bacteria, such as M. tuberculosis in macrophages, but the role of P2 receptors in killing sepsis-causing extracellular bacteria is unknown. Our preliminary data demonstrated that ATP increases the killing of sepsis-causing extracellular bacteria, such as E. coli or S. aureus; however, this killing effect is not mediated by P2X7 receptors but instead it is mediated by P2X4 receptors. Using intraperitoneally administered ivermectin, a positive allosteric modulator of P2X4 receptors, we demonstrated that P2X4 receptor activation protected mice against bacterial dissemination, inflammation, and mortality during abdominal, polymicrobial sepsis in mice. Here we will test the hypothesis that intravenously injected ivermection protects mice against sepsis-induced bacterial dissemination, inflammation, organ injury, and mortality. To address this hypothesis, we propose two Specific Aims. In Specific Aim 1, we will test the efficacy of ivermectin in preventing mortality in polymicrobial sepsis induced by cecal ligation and puncture in mice. In Specific Aim 2, we will delineate the effect of ivermectin on bacterial growth, inflammation and organ injury in sepsis. We expect that ivermectin will reduce bacterial growth, inflammation, organ damage, and mortality in septic mice. The long-term goal of this study is to develop ivermectin as a safe and effective treatment option for the management of patients with sepsis.