title: Staphylococcus aureus leukotoxin GH promotes formation of neutrophil extracellular traps.
abstract: Staphylococcus aureus secretes numerous virulence factors that facilitate evasion of the host immune system. Among these molecules are pore-forming cytolytic toxins, including Panton-Valentine leukocidin (PVL), leukotoxin GH (LukGH; also known as LukAB), leukotoxin DE, and γ-hemolysin. PVL and LukGH have potent cytolytic activity in vitro, and both toxins are proinflammatory in vivo. Although progress has been made toward elucidating the role of these toxins in S. aureus virulence, our understanding of the mechanisms that underlie the proinflammatory capacity of these toxins, as well as the associated host response toward them, is incomplete. To address this deficiency in knowledge, we assessed the ability of LukGH to prime human PMNs for enhanced bactericidal activity and further investigated the impact of the toxin on neutrophil function. We found that, unlike PVL, LukGH did not prime human neutrophils for increased production of reactive oxygen species nor did it enhance binding and/or uptake of S. aureus. Unexpectedly, LukGH promoted the release of neutrophil extracellular traps (NETs), which, in turn, ensnared but did not kill S. aureus. Furthermore, we found that electropermeabilization of human neutrophils, used as a separate means to create pores in the neutrophil plasma membrane, similarly induced formation of NETs, a finding consistent with the notion that NETs can form during nonspecific cytolysis. We propose that the ability of LukGH to promote formation of NETs contributes to the inflammatory response and host defense against S. aureus infection.
authors.affiliation: Laboratory of Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840.
authors.forename: Natalia
authors.initials: N
authors.lastname: Malachowa
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kobayashi
authors.forename: Brett
authors.initials: B
authors.lastname: Freedman
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
mesh_terms: D001426:Bacterial Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000302:isolation & purification / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D018274:Electroporation; D005089:Exocytosis / Q000187:drug effects; D005110:Extracellular Space; D006801:Humans; D007956:Leukocidins / Q000302:isolation & purification / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure; D009895:Opsonin Proteins / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000276:immunology; D013211:Staphylococcus aureus / Q000737:chemistry / Q000276:immunology / Q000472:pathogenicity*; D013481:Superoxides / Q000378:metabolism; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D007956:Leukocidins; D009895:Opsonin Proteins; C586430:leukocidin AB, Staphylococcus aureus; D013481:Superoxides; D009195:Peroxidase