Mortality from bacterial sepsis remains unacceptably high despite remarkable advances in antibiotic therapy and supportive care. Recent post-mortem studies have clearly revealed that most patients displayed unresolved septic foci at death, suggesting that patients were unable to effectively eradicate invading pathogens. A barrier limiting breakthrough strategic development exists because the current conceptual and scientific basis for antimicrobial therapy centers solely on the bacterium, yet the mechanistic insight of host- pathogen interaction remains poorly understood. Host-directed strategies to boost phagocyte bactericidal activity and reverse pathogen-induced immunosuppression may replicate the success of cancer immunotherapy in the field of infectious diseases. With this in mind, we have identified p120 catenin (p120), highly expressed in macrophages, to be crucial in bacterial clearance. Preliminary data in this grant indicate that p120 loss in alveolar macrophages obtained from septic patients correlated closely with the bacterial loads and respiratory dysfunction. Specific macrophage deletion of p120 resulted in dramatic increase in bacterial load in the lung and liver abscess in polymicrobial sepsis induced by cecal ligation and puncture in mice. Importantly, depletion of p120 in human alveolar macrophages and murine bone marrow-derived macrophages nearly completely blocked phagocytosis of bacteria. Further study revealed that incubation of bone marrow- derived macrophages with bacteria induced rapid p120 sumoylation and expression of non-sumoylatable p120 mutant in p120-depleted mouse bone marrow-derived macrophages completely prevented phagocytosis of E. coli. These intriguing findings support the hypothesis that p120 expression in macrophages is an important determinant of eradication of bacterial infections and therefore outcome of sepsis. We will test this hypothesis via the following specific aims: 1) To evaluate the role of macrophage p120 in bacterial clearance and lung injury during sepsis. 2) To elucidate the molecular mechanisms by which p120 controls bacterial clearance. 3) To examine the therapeutic potential of targeting macrophage p120 for treatment of septic injury. This proposal will decipher a previously unrecognized mechanism controlling the interaction of host and bacterial pathogens. The completion of the proposed studies will promote the development of novel immune-enhancing therapeutic strategies to improve clinical outcomes and survival for the treatment of bacterial sepsis.