title: The TIR Homologue Lies near Resistance Genes in Staphylococcus aureus, Coupling Modulation of Virulence and Antimicrobial Susceptibility.
abstract: Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors are essential for initiating and propagating the eukaryotic innate immune signaling cascade. Here, we investigate TirS, a Staphylococcus aureus TIR mimic that is part of a novel bacterial invasion mechanism. Its ectopic expression in eukaryotic cells inhibited TLR signaling, downregulating the NF-kB pathway through inhibition of TLR2, TLR4, TLR5, and TLR9. Skin lesions induced by the S. aureus knockout tirS mutant increased in a mouse model compared with wild-type and restored strains even though the tirS-mutant and wild-type strains did not differ in bacterial load. TirS also was associated with lower neutrophil and macrophage activity, confirming a central role in virulence attenuation through local inflammatory responses. TirS invariably localizes within the staphylococcal chromosomal cassettes (SCC) containing the fusC gene for fusidic acid resistance but not always carrying the mecA gene. Of note, sub-inhibitory concentration of fusidic acid increased tirS expression. Epidemiological studies identified no link between this effector and clinical presentation but showed a selective advantage with a SCCmec element with SCC fusC/tirS. Thus, two key traits determining the success and spread of bacterial infections are linked.
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Patot
authors.affiliation: Laboratory of Molecular Microbiology and Structural Biochemistry, University of Lyon, CNRS UMR5086, Lyon, France.
authors.forename: Paul
authors.initials: PR
authors.lastname: Imbert
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Baude
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martins Simões
authors.affiliation: Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Campergue
authors.affiliation: Laboratory of Molecular Microbiology and Structural Biochemistry, University of Lyon, CNRS UMR5086, Lyon, France.
authors.forename: Arthur
authors.initials: A
authors.lastname: Louche
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.|Laboratory of Phytopathology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Reindert
authors.identifier: 0000-0003-0049-3768
authors.initials: R
authors.lastname: Nijland
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Bès
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tristan
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Laurent
authors.affiliation: Genomic Research Laboratory, University of Geneva Hospitals, Geneva, Switzerland.
authors.forename: Adrien
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Genomic Research Laboratory, University of Geneva Hospitals, Geneva, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Schrenzel
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France.
authors.forename: François
authors.identifier: 0000-0001-9412-7106
authors.initials: F
authors.lastname: Vandenesch
authors.affiliation: Laboratory of Molecular Microbiology and Structural Biochemistry, University of Lyon, CNRS UMR5086, Lyon, France.
authors.forename: Suzana
authors.identifier: 0000-0001-5149-7756
authors.initials: SP
authors.lastname: Salcedo
authors.affiliation: Genomic Research Laboratory, University of Geneva Hospitals, Geneva, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: François
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lina
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D005672:Fusidic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D009504:Neutrophils / Q000276:immunology; D046915:Penicillin-Binding Proteins / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D051193:Toll-Like Receptors / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics* / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D046915:Penicillin-Binding Proteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C000621245:TirS protein, Staphylococcus aureus; D051193:Toll-Like Receptors; D037521:Virulence Factors; C487789:mecA protein, Staphylococcus aureus; D005672:Fusidic Acid