Shigella induces mitochondrial dysfunction and cell death in nonmyleoid cells.
Shigella rapidly kills myeloid cells via a caspase-1 inflammasome-dependent cell death mechanism. However, despite a critical role for nonmyeloid cells in the physiopathology of Shigella infection, the mechanism by which Shigella kills nonmyeloid cells remains uncharacterized. Here we demonstrate that, in nonmyeloid cells, Shigella infection induces loss of mitochondrial inner membrane potential, mitochondrial damage, and necrotic cell death through a pathway dependent on Bnip3 and cyclophilin D, two molecules implicated in the host oxidative stress responses. This mitochondrial cell death mechanism was potently counterbalanced by a Nod1-dependent Rip2/IKKbeta/NF-kappaB signaling pathway activated by the pathogen in the first hours of infection. Our results suggest that in nonmyeloid cells, oxidative stress pathways and signaling triggered by an intracellular bacterial pathogen are tightly linked and demonstrate the existence of specific Shigella-induced prodeath and prosurvival pathways converging at the mitochondria to control a necrotic cell death program.
Carneiro
Leticia A M
LA
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Travassos
Leonardo H
LH
Soares
Fraser
F
Tattoli
Ivan
I
Magalhaes
Joao G
JG
Bozza
Marcelo T
MT
Plotkowski
Maria C
MC
Sansonetti
Philippe J
PJ
Molkentin
Jeffery D
JD
Philpott
Dana J
DJ
Girardin
Stephen E
SE
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D021983:Cyclophilins / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology*; D008954:Models, Biological; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012760:Shigella / Q000472:pathogenicity*; D015398:Signal Transduction; D000097322:Peptidyl-Prolyl Isomerase D
D021983:Cyclophilins; D008565:Membrane Proteins; D053474:Nod1 Signaling Adaptor Protein; D011518:Proto-Oncogene Proteins; C090121:BNIP3 protein, human; C119067:NOD1 protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D