Shigella flexneri induces apoptosis in infected macrophages

THE Gram-negative bacterial pathogen Shigella flexneri causes dysentery by invading the human colonic mucosa¹. Bacteria are phagocytosed by enterocytes², escape from the phagosome into the cytoplasm³ and spread to adjacent cells⁴. After crossing the epithelium, Shigella reaches the lamina propria of intestinal villi, the first line of defence. This tissue is densely populated with phagocytes that are killed in great numbers, resulting in abscesses^5,6. The genes required for cell invasion⁷ and macrophage killing² are located on a 220-kilobase plasmid. We report here on the mechanism of cytotoxicity used by S. flexneri to kill macrophages. Each of four different strains was tested for its capacity to induce cell death. An invasive strain induced programmed cell death (apoptosis^8,9), whereas its non-invasive, plasmid-cured isogenic strain was not toxic; neither was a mutant in ipa B (ref. 10) (invasion protein antigen), a gene necessary for entry. A non-invasive strain expressing the haemolysin operon of Escherichia coli¹¹ induced accidental cell death (necrosis), demonstrating that other bacterial cytotoxic mechanisms do not lead to apoptosis. This is the first evidence that an invasive bacterial pathogen can induce suicide in its host cells.