ABSTRACT Legionella pneumophila is an infectious bacterium that causes Legionnaire’s disease and remains a major cause of morbidity and mortality in the immunocompromised individuals such as the elderly and cancer patients. Macrophages are the main immune cells that can clear Legionella after activation of the canonical Nlrc4/Naip5 inflammasome. Caspase-11 is a component of the non-canonical inflammasome and mice lacking caspase-11 allow significant Legionella replication in their macrophages. Down-regulation of the homologous caspase in human macrophages increases their permissiveness to Legionella. Our preliminary data show that caspase-11 is necessary for fusion of the Legionella-containing vacuole with the lysosomes via a mechanism that requires the polymerization and depolymerization of actin. Using state-of-the-art techniques including 3D confocal microscopy and high resolution SIM-S microscopy, RNA seq and proteomics analyses, we identified new molecules that are cleaved by caspase-11 and regulate restriction of Legionella in macrophages. This proposal will investigate the molecular mechanisms leading to caspase-11-mediated clearing of Legionella infection.