Previous studies performed with vacuolar pathogens that mislocalize to the cytosol highlighted differences between immune cells and nonimmune cells with respect to the ability to restrict pathogens in the cytosol. S. enterica ΔsifA mutants, which access the cytosol due to loss of vacuole integrity (43), appear to be killed in macrophages but not HeLa cells (3). Legionella pneumophila ΔsdhA mutants, which similarly mislocalize to the host cytosol (4), also display cell-specific survival defects (44) and are ultimately killed in the cytosol, resulting in activation of the AIM2 inflammasome (45). Our genetic screen also identified mutants with differential survival defects in different cell types and suggested that, similarly to the phagosomal killing capacity results, professional phagocytes such as macrophages may have more-potent cytosolic CADs (Fig. 1B). This may translate directly to virulence, as evidenced by the results seen with pdhC::Tn mutants, which were slowly cleared from macrophages but were capable of forming plaques in fibroblasts consistent with their improved survival in the cytosol of these cells (Fig. 2A and B). L. monocytogenes and other cytosolic pathogens likely employ various strategies to counter CADs in different cell types.