title: Staphylococcus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils.
abstract: Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by Staphylococcus aureus that has recently been associated with necrotizing pneumonia. In the present study, we report that in vitro, PVL induces polymorphonuclear cell death by necrosis or by apoptosis, depending on the PVL concentration. PVL-induced apoptosis was associated with a rapid disruption of mitochondrial homeostasis and activation of caspase-9 and caspase-3, suggesting that PVL-induced apoptosis is preferentially mediated by the mitochondrial pathway. Polymorphonuclear cell exposure to PVL leads to mitochondrial localization of the toxin, whereas Bax, 1 of the 2 essential proapoptotic members of the Bcl-2 family, was still localized in the cytosol. Addition of PVL to isolated mitochondria induced the release of the apoptogenic proteins cytochrome c and Smac/DIABLO. Therefore, we suggest that PVL, which belongs to the pore-forming toxin family, could act at the mitochondrion level by creating pores in the mitochondrial outer membrane. Furthermore, LukS-PV, 1 of the 2 components of PVL, was detected in lung sections of patients with necrotizing pneumonia together with DNA fragmentation, suggesting that PVL induces apoptosis in vivo and thereby is directly involved in the pathophysiology of necrotizing pneumonia.
authors.affiliation: Centre National de Référence des Staphylocoques, INSERM E0230, Lyon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Genestier
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Michallet
authors.forename: Gilles
authors.initials: G
authors.lastname: Prévost
authors.forename: Gregory
authors.initials: G
authors.lastname: Bellot
authors.forename: Lara
authors.initials: L
authors.lastname: Chalabreysse
authors.forename: Simone
authors.initials: S
authors.lastname: Peyrol
authors.forename: Françoise
authors.initials: F
authors.lastname: Thivolet
authors.forename: Jerome
authors.initials: J
authors.lastname: Etienne
authors.forename: Gérard
authors.initials: G
authors.lastname: Lina
authors.forename: François M
authors.initials: FM
authors.lastname: Vallette
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.forename: Laurent
authors.initials: L
authors.lastname: Genestier
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005098:Exotoxins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D007956:Leukocidins / Q000494:pharmacology*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009336:Necrosis; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects* / Q000382:microbiology; D011023:Pneumonia, Staphylococcal / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D001427:Bacterial Toxins; C412403:DIABLO protein, human; D005098:Exotoxins; D047908:Intracellular Signaling Peptides and Proteins; D007956:Leukocidins; D024101:Mitochondrial Proteins; C078284:Panton-Valentine leukocidin; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c