title: Disruption of the sigS gene attenuates the local innate immune response to Staphylococcus aureus in a mouse mastitis model.
abstract: Staphylococcus aureus (S. aureus) is a major pathogen involved in ruminant mastitis and present worldwide. Clinical signs of S. aureus mastitis vary considerably and are largely dependent on strain-specific factors. A comparison of two S. aureus strains that reproducibly induced either severe (O11) or mild (O46) mastitis in ewes revealed that the transcriptional regulator sigS was mutated in O46 (Le Maréchal et al., 2011. PLoS One. 6 (11) e27354. doi:10.1371/journal.pone.0027354). In the present paper, we analysed the sigS sequence in 18 other S. aureus strains isolated from goat or ewe mastitis and found a 4-bp deletion similar to that of the O46 sigS gene in three strains associated with subclinical ewe mastitis. This sigS gene was disrupted in strain O11 (O11ΔsigS), so our aim was to investigate its involvement in the severity of infections in the context of mastitis. The wild type (wt) and mutant strains were then characterized in vitro to determine the involvement of sigS in the response S. aureus under various stress conditions, and assess its influence on the cytotoxicity of the pathogen, its invasive capacity and biofilm formation. The strains were compared in vivo in an experimental mouse mastitis model in which clinical signs and cytokine production were evaluated at 24h post-infection. While no significant differences in the effect on bacterial growth between O11 and O11ΔsigS were observed either in vitro or in vivo, a significantly weaker in vivo production of interleukin (IL)-1α, IL-1β, and Tumor Necrosis Factor (TNF)-α was measured in the mammary glands infected with the mutant strain, suggesting that infection with O11ΔsigS induced an attenuated local innate immune response. These results suggest an impact of sigS disruption on S. aureus pathogenesis in a ruminant mastitis context. This disruption is probably involved in, and may partly explain, the milder symptoms previously observed in S. aureus O46-induced mastitis in ewes.
authors.affiliation: INRA, UMR 1253 STLO, 65 rue de Saint Brieuc, 35042 Rennes Cedex, France; Agrocampus Ouest, UMR1253 STLO, 85 rue de Saint Brieuc, 35042 Rennes Cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Peton
authors.affiliation: Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Breyne
authors.affiliation: INRA, UMR 1253 STLO, 65 rue de Saint Brieuc, 35042 Rennes Cedex, France; Agrocampus Ouest, UMR1253 STLO, 85 rue de Saint Brieuc, 35042 Rennes Cedex, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Rault
authors.affiliation: Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Demeyere
authors.affiliation: INRA, UMR 1253 STLO, 65 rue de Saint Brieuc, 35042 Rennes Cedex, France; Agrocampus Ouest, UMR1253 STLO, 85 rue de Saint Brieuc, 35042 Rennes Cedex, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Berkova
authors.affiliation: Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Meyer
authors.affiliation: INRA, UMR 1253 STLO, 65 rue de Saint Brieuc, 35042 Rennes Cedex, France; Agrocampus Ouest, UMR1253 STLO, 85 rue de Saint Brieuc, 35042 Rennes Cedex, France.
authors.forename: Sergine
authors.initials: S
authors.lastname: Even
authors.affiliation: INRA, UMR 1253 STLO, 65 rue de Saint Brieuc, 35042 Rennes Cedex, France; Agrocampus Ouest, UMR1253 STLO, 85 rue de Saint Brieuc, 35042 Rennes Cedex, France. Electronic address: yves.leloir@rennes.inra.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Loir
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006041:Goats; D007113:Immunity, Innate / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000276:immunology / Q000382:microbiology; D008413:Mastitis / Q000276:immunology / Q000382:microbiology / Q000662:veterinary*; D051379:Mice; D012756:Sheep; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000662:veterinary*; D013211:Staphylococcus aureus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology
chemical_list: D001426:Bacterial Proteins
keywords: Inflammatory response; Mastitis; Mouse model; Staphylococcus aureus; Transcriptional regulator; Virulence; σ factor