Salmonella enterica Infection Stimulates Macrophages to Hemophagocytose

Hemophagocytes are cells of the monocyte lineage that have engulfed erythrocytes and leukocytes. Hemophagocytes frequently accumulate in patients with severe acute bacterial infections, such as those caused by Salmonella enterica, Brucella abortus, and Mycobacterium tuberculosis. The relationship between hemophagocytosis and infection is not well understood. In the murine liver, S. enterica serovar Typhimurium resides within hemophagocytic macrophages containing leukocytes. Here we show that S. Typhimurium also resides within hemophagocytes containing erythrocytes. In cell culture, S. Typhimurium benefits from residence within hemophagocytes by accessing iron, but why macrophages hemophagocytose is unknown. We show that treatment of macrophages with a cocktail of the proinflammatory cytokine interferon gamma (IFN-γ) and lipopolysaccharide (LPS) stimulates engulfment of nonsenescent erythrocytes. Exposure of resting or IFN-γ-treated macrophages to live, but not to heat-killed, S. Typhimurium cells also stimulates erythrocyte engulfment. Single-cell analyses show that S. Typhimurium-infected macrophages are more likely to erythrophagocytose and that infected macrophages engulf more erythrocytes than uninfected macrophages within the same culture well. In addition, macrophages containing erythrocytes harbor more bacteria. However, S. Typhimurium does not promote macrophage engulfment of polystyrene beads, suggesting a role for a ligand on the target cell. Finally, neither of the two S. Typhimurium type 3 secretion systems, T3SS1 or T3SS2, is fully required for hemophagocytosis. These results indicate that infection of macrophages with live S. Typhimurium cells stimulates hemophagocytosis.