We now recognize that the autophagy machinery functions in a multitude of non-canonical biological pathways, including the host defense to extracellular threats, such as pathogens. We have identified a form of non-canonical autophagy termed LC3-associated phagocytosis (LAP), wherein phagosomes containing engulfed particles, including pathogens and dying cells, recruit elements of the autophagy pathway to facilitate phagosome maturation, digestion of cargo, and modulation of innate immunity. We have characterized Rubicon as a LAP-specific, autophagy-independent molecule, allowing the study of the unique role of LAP. To better understand host factors that may play a role in infection, we investigated the role of Rubicon during Salmonella enterica Typhimurium infection. Macrophages lacking Rubicon failed to control S. enterica Typhimurium and produced a markedly decreased ability to produce free radicals during infection compared to wild type macrophages. Rubicon-deficient cells also displayed a hyperactivation of canonical Nf- K b signaling, demonstrating a failure to coordinate an appropriate inflammatory reaction. Rubicon-/mice demonstrate that Rubicon is essential for several aspects of pathology including replication control and immunological response.