title: Intracellular bacteriolysis triggers a massive apoptotic cell death in Shigella-infected epithelial cells.
abstract: Infected epithelial cells, which act as a first barrier against pathogens, seldom undergo apoptosis. Rather, infected epithelial cells undergo a slow cell death that displays hallmarks of necrosis. Here, we demonstrate that rapid intracellular lysis of Shigella flexneri, provoked by either the use of a diaminopimelic acid auxotroph mutant or treatment of infected cells with antibiotics of the beta-lactam family, resulted in a massive and rapid induction of apoptotic cell death. This intracellular bacteriolysis-mediated apoptotic death (IBAD) was characterized by the specific involvement of the mitochondrial-dependent cytochrome c/Apaf-1 axis that resulted in the activation of caspases-3, -6 and -9. Importantly, Bcl-2 family members and the NF-kappaB pathway seemed to be critical modulators of IBAD. Finally, we identified that IBAD was also triggered by Salmonella enterica serovar Typhimurium but not by the Gram-positive bacteria, Listeria monocytogenes. Together, our results demonstrate that, contrary to previous findings, epithelial cells are intrinsically able to mount an efficient apoptotic cell death response following infection. Indeed, apoptosis in normal circumstances is masked by powerful anti-apoptotic mechanisms, which are overcome in IBAD. Our results also uncover an unexpected consequence of the treatment of infected cells with certain classes of antibiotics.
authors.affiliation: Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tattoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Lembo-Fazio
authors.forename: Giulia
authors.initials: G
authors.lastname: Nigro
authors.forename: Leticia A M
authors.initials: LA
authors.lastname: Carneiro
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferraro
authors.forename: Giacomo
authors.initials: G
authors.lastname: Rossi
authors.forename: Maria Celeste
authors.initials: MC
authors.lastname: Martino
authors.forename: Maria Egle
authors.initials: ME
authors.lastname: de Stefano
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Maria Lina
authors.initials: ML
authors.lastname: Bernardini
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D001433:Bacteriolysis; D053148:Caspase 3 / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000502:physiology*; D012763:Shigella flexneri / Q000187:drug effects / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D016328:NF-kappa B; D045304:Cytochromes c; D053148:Caspase 3; D053178:Caspase 6; D053453:Caspase 9