title: Superoxide anions produced by Streptococcus pyogenes group A-stimulated keratinocytes are responsible for cellular necrosis and bacterial growth inhibition.
abstract: Gram-positive Streptococcus pyogenes (group A Streptococcus or GAS) is a major skin pathogen and interacts with keratinocytes in cutaneous tissues. GAS can cause diverse suppurative and inflammatory infections, such as cellulitis, a common acute bacterial dermo-hypodermitis with a high morbidity. Bacterial isolation yields from the lesions are low despite the strong local inflammation observed, raising numerous questions about the pathogenesis of the infection. Using an in vitro model of GAS-infected keratinocytes, we show that the major ROS produced is the superoxide anion ([Formula: see text]), and that its production is time- and dose-dependent. Using specific modulators of ROS production, we show that [Formula: see text] is mainly synthesized by the cytoplasmic NADPH oxidase. Superoxide anion production leads to keratinocyte necrosis but incomplete inhibition of GAS growth, suggesting that GAS may be partially resistant to the oxidative burst. In conclusion, GAS-stimulated keratinocytes are able to develop an innate immune response based on the production of ROS. This local immune response limits GAS development and induces keratinocyte cell death, resulting in the skin lesions observed in patients with cellulitis.
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Regnier
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Grange
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Ollagnier
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Crickx
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Elie
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France Service d'Immunologie Biologique, Hôpital Cochin-Pavillon Achard, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France Service d'Immunologie Biologique, Hôpital Cochin-Pavillon Achard, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France Service de Bactériologie, Centre National de Référence des Streptocoques, Groupe Hospitalier Paris Centre Cochin-Hôtel Dieu-Broca, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Plainvert
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France Service de Bactériologie, Centre National de Référence des Streptocoques, Groupe Hospitalier Paris Centre Cochin-Hôtel Dieu-Broca, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Poyart
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France Service d'Immunologie Biologique, Hôpital Cochin-Pavillon Achard, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: Institut Cochin, INSERM U1016, Faculté de Médecine, Université Paris Descartes, Paris, France Service de Dermatologie-Vénéréologie, Hôpital Cochin-Pavillon Tarnier, Paris, France nicolas.dupin@cch.aphp.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupin
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D015603:Keratinocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009336:Necrosis; D010084:Oxidation-Reduction; D013290:Streptococcal Infections / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000254:growth & development / Q000276:immunology*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D006131:Growth Inhibitors; D013481:Superoxides; D019255:NADPH Oxidases
keywords: ROS; Streptococcus pyogenes; cell death; cellulitis; inflammation