title: The catabolite control protein E (CcpE) affects virulence determinant production and pathogenesis of Staphylococcus aureus.
abstract: Carbon metabolism and virulence determinant production are often linked in pathogenic bacteria, and several regulatory elements have been reported to mediate this linkage in Staphylococcus aureus. Previously, we described a novel protein, catabolite control protein E (CcpE) that functions as a regulator of the tricarboxylic acid cycle. Here we demonstrate that CcpE also regulates virulence determinant biosynthesis and pathogenesis. Specifically, deletion of ccpE in S. aureus strain Newman revealed that CcpE affects transcription of virulence factors such as capA, the first gene in the capsule biosynthetic operon; hla, encoding α-toxin; and psmα, encoding the phenol-soluble modulin cluster α. Electrophoretic mobility shift assays demonstrated that CcpE binds to the hla promoter. Mice challenged with S. aureus strain Newman or its isogenic ΔccpE derivative revealed increased disease severity in the ΔccpE mutant using two animal models; an acute lung infection model and a skin infection model. Complementation of the mutant with the ccpE wild-type allele restored all phenotypes, demonstrating that CcpE is negative regulator of virulence in S. aureus.
authors.affiliation: From the Institute of Medical Microbiology and Hygiene, University of Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hartmann
authors.affiliation: the Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université Montpellier 2, CNRS, UMR 5235, 34090 Montpellier, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Baronian
authors.affiliation: the Institute of Immunology, University of Münster, 48149 Münster, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nippe
authors.affiliation: the Department of Internal Medicine V-Pulmonology, Allergology and Critical Care Medicine, Saarland University Medical Centre, 66421 Homburg/Saar, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Voss
authors.affiliation: the Institute of Medical Microbiology, University of Zürich, 8006 Zürich, Switzerland.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schulthess
authors.affiliation: the Institute of Medical Microbiology and Hygiene, University Hospital of Tübingen, 72076 Tübingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolz
authors.affiliation: From the Institute of Medical Microbiology and Hygiene, University of Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Eisenbeis
authors.affiliation: the Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schmidt-Hohagen
authors.affiliation: From the Institute of Medical Microbiology and Hygiene, University of Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Gaupp
authors.affiliation: the Department of Dermatology, University of Münster, 48149 Münster, Germany, and.
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkötter
authors.affiliation: the Department of Internal Medicine V-Pulmonology, Allergology and Critical Care Medicine, Saarland University Medical Centre, 66421 Homburg/Saar, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Beisswenger
authors.affiliation: the Department of Internal Medicine V-Pulmonology, Allergology and Critical Care Medicine, Saarland University Medical Centre, 66421 Homburg/Saar, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Bals
authors.affiliation: the School of Veterinary Medicine and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska 68583-0903.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Somerville
authors.affiliation: From the Institute of Medical Microbiology and Hygiene, University of Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: the Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université Montpellier 2, CNRS, UMR 5235, 34090 Montpellier, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Molle
authors.affiliation: From the Institute of Medical Microbiology and Hygiene, University of Saarland, 66421 Homburg/Saar, Germany, markus.bischoff@uks.eu.
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D005810:Multigene Family; D010860:Pigments, Biological / Q000096:biosynthesis; D012329:RNA, Bacterial / Q000235:genetics; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000472:pathogenicity*; D014158:Transcription, Genetic; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D010860:Pigments, Biological; D012329:RNA, Bacterial; C096035:RNAIII, Staphylococcus aureus; D037521:Virulence Factors
keywords: Bacterial Pathogenesis; Staphylococcus aureus (S. aureus); Transcription Regulation; Tricarboxylic Acid Cycle (TCA Cycle) (Krebs Cycle); Virulence Factor