title: Staphylococcal Enterotoxin O Exhibits Cell Cycle Modulating Activity.
abstract: Maintenance of an intact epithelial barrier constitutes a pivotal defense mechanism against infections. Staphylococcus aureus is a versatile pathogen that produces multiple factors including exotoxins that promote tissue alterations. The aim of the present study is to investigate the cytopathic effect of staphylococcal exotoxins SEA, SEG, SEI, SElM, SElN and SElO on the cell cycle of various human cell lines. Among all tested exotoxins only SEIO inhibited the proliferation of a broad panel of human tumor cell lines in vitro. Evaluation of a LDH release and a DNA fragmentation of host cells exposed to SEIO revealed that the toxin does not induce necrosis or apoptosis. Analysis of the DNA content of tumor cells synchronized by serum starvation after exposure to SEIO showed G0/G1 cell cycle delay. The cell cycle modulating feature of SEIO was confirmed by the flow cytometry analysis of synchronized cells exposed to supernatants of isogenic S. aureus strains wherein only supernatant of the SElO producing strain induced G0/G1 phase delay. The results of yeast-two-hybrid analysis indicated that SEIO's potential partner is cullin-3, involved in the transition from G1 to S phase. In conclusion, we provide evidence that SEIO inhibits cell proliferation without inducing cell death, by delaying host cell entry into the G0/G1 phase of the cell cycle. We speculate that this unique cell cycle modulating feature allows SEIO producing bacteria to gain advantage by arresting the cell cycle of target cells as part of a broader invasive strategy.
authors.affiliation: International Center for Infectiology ResearchLyon, France; CNRS UMR5308, Inserm U1111, Ecole Normale Supérieure de Lyon - Université Lyon 1Lyon, France; Institut des Agents Infectieux, Hospices Civils de LyonLyon, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hodille
authors.affiliation: UMR1253 STLO, Agrocampus Ouest, Institut National de la Recherche AgronomiqueRennes, France; Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryMoscow, Russia.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Alekseeva
authors.affiliation: UMR1253 STLO, Agrocampus Ouest, Institut National de la Recherche Agronomique Rennes, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Berkova
authors.affiliation: International Center for Infectiology ResearchLyon, France; CNRS UMR5308, Inserm U1111, Ecole Normale Supérieure de Lyon - Université Lyon 1Lyon, France.
authors.forename: Asma
authors.initials: A
authors.lastname: Serrier
authors.affiliation: International Center for Infectiology ResearchLyon, France; CNRS UMR5308, Inserm U1111, Ecole Normale Supérieure de Lyon - Université Lyon 1Lyon, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Badiou
authors.affiliation: iRTSV-BGE, Université Grenoble AlpesGrenoble, France; CEA, iRTSV-BGEGrenoble, France; Biologie à Grande Echelle, Institut National de la Santé et de la Recherche MédicaleGrenoble, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gilquin
authors.affiliation: iRTSV-BGE, Université Grenoble AlpesGrenoble, France; CEA, iRTSV-BGEGrenoble, France; Biologie à Grande Echelle, Institut National de la Santé et de la Recherche MédicaleGrenoble, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Brun
authors.affiliation: International Center for Infectiology ResearchLyon, France; CNRS UMR5308, Inserm U1111, Ecole Normale Supérieure de Lyon - Université Lyon 1Lyon, France; Institut des Agents Infectieux, Hospices Civils de LyonLyon, France.
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.affiliation: Jenomic Research Institute, Carmel CA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Terman
authors.affiliation: International Center for Infectiology ResearchLyon, France; CNRS UMR5308, Inserm U1111, Ecole Normale Supérieure de Lyon - Université Lyon 1Lyon, France; Institut des Agents Infectieux, Hospices Civils de LyonLyon, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lina
keywords: G0/G1 phase delay; Staphylococcus aureus; cell cycle alteration; cullin-3; cyclomodulin; enterotoxin O