Going around in circles: virulence plasmids in enteric pathogens

The Gram-negative bacterial pathogen Shigella flexneri causes dysentery by invading the human colonic mucosa. Bacteria are phagocytosed by enterocytes, escape from the phagosome into the cytoplasm and spread to adjacent cells. 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. The genes required for cell invasion and macrophage killing 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), whereas its non-invasive, plasmidcured 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 coli 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.

Shigella spp. are gram-negative pathogenic bacteria that evolved from harmless enterobacterial relatives and may cause devastating diarrhea upon ingestion. Research performed over the last 25 years revealed that a type III secretion system (T3SS) encoded on a large plasmid is a key virulence factor of Shigella flexneri. The T3SS determines the interactions of S. flexneri with intestinal cells by consecutively translocating two sets of effector proteins into the target cells. Thus, S. flexneri controls invasion into EC, intra- and intercellular spread, macrophage cell death, as well as host inflammatory responses. Some of the translocated effector proteins show novel biochemical activities by which they intercept host cell signal transduction pathways. An understanding of the molecular mechanisms underlying Shigella pathogenesis will foster the development of a safe and efficient vaccine, which, in parallel with improved hygiene, should curb infections by this widespread pathogen.