Loss of the actin filament capping protein CapG has no apparent effect on the phenotype of mice maintained under sterile conditions; however, bone marrow-derived macrophages from CapG(-/-) mice exhibited distinct motility defects. We examined the ability of CapG(-/-) mice to clear two intracellular bacteria, Listeria monocytogenes and Salmonella enterica serovar Typhimurium. The 50% lethal dose of Listeria was 10-fold lower for CapG(-/-) mice than for CapG(+/+) mice (6 x 10(3) CFU for CapG(-/-) mice and 6 x 10(4) CFU for CapG(+/+) mice), while no difference was observed for Salmonella: The numbers of Listeria cells in the spleens and livers were significantly higher in CapG(-/-) mice than in CapG(+/+) mice at days 5 to 9, while the bacterial counts were identical on day 5 for Salmonella-infected mice. Microscopic analysis revealed qualitatively similar inflammatory responses in the spleens and livers of the two types of mice. Specific immunofluorescence staining analyzed by fluorescence-activated cell sorting revealed similar numbers of macrophages and dendritic cells in infected CapG(-/-) and CapG(+/+) spleens. However, analysis of bone marrow-derived macrophages revealed a 50% reduction in the rate of phagocytosis of Listeria in CapG(-/-) cells but a normal rate of phagocytosis of Salmonella: Stimulation of bone marrow-derived dendritic cells with granulocyte-macrophage colony-stimulating factor resulted in a reduction in the ruffling response of CapG(-/-) cells compared to the response of CapG(+/+) cells, and CapG(-/-) bone-marrowed derived neutrophils migrated at a mean speed that was nearly 50% lower than the mean speed of CapG(+/+) neutrophils. Our findings suggest that specific motility deficits in macrophages, dendritic cells, and neutrophils render CapG(-/-) mice more susceptible than CapG(+/+) mice to Listeria infection.