Intracellular bacteriolysis triggers a massive apoptotic cell death in Shigella-infected epithelial cells.
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.
Tattoli
Ivan
I
Dipartimento di Biologia Cellulare e dello Sviluppo, Sapienza-Università di Roma, Via dei Sardi 70, 00185 Roma, Italy.
Lembo-Fazio
Luigi
L
Nigro
Giulia
G
Carneiro
Leticia A M
LA
Ferraro
Elisabetta
E
Rossi
Giacomo
G
Martino
Maria Celeste
MC
de Stefano
Maria Egle
ME
Cecconi
Francesco
F
Girardin
Stephen E
SE
Philpott
Dana J
DJ
Bernardini
Maria Lina
ML
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*
D000900:Anti-Bacterial Agents; D016328:NF-kappa B; D045304:Cytochromes c; D053148:Caspase 3; D053178:Caspase 6; D053453:Caspase 9