title: Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants.
abstract: Sepsis caused by Gram-positive bacterial pathogens is a major fatal disease but its molecular basis remains elusive. Toll-like receptor 2 (TLR2) has been implicated in the orchestration of inflammation and sepsis but its role appears to vary for different pathogen species and clones. Accordingly, Staphylococcus aureus clinical isolates differ substantially in their capacity to activate TLR2. Here we show that strong TLR2 stimulation depends on high-level production of phenol-soluble modulin (PSM) peptides in response to the global virulence activator Agr. PSMs are required for mobilizing lipoproteins, the TLR2 agonists, from the staphylococcal cytoplasmic membrane. Notably, the course of sepsis caused by PSM-deficient S. aureus is similar in wild-type and TLR2-deficient mice, but TLR2 is required for protection of mice against PSM-producing S. aureus. Thus, a crucial role of TLR2 depends on agonist release by bacterial surfactants. Modulation of this process may lead to new therapeutic strategies against Gram-positive infections.
authors.affiliation: Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hanzelmann
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Hwang-Soo
authors.initials: HS
authors.lastname: Joo
authors.affiliation: Proteome Center Tübingen, Interfaculty Institute of Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Mirita
authors.initials: M
authors.lastname: Franz-Wachtel
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Straße 2, Würzburg 97080, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hertlein
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanovic
authors.affiliation: Proteome Center Tübingen, Interfaculty Institute of Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Macek
authors.affiliation: Department of Medical Microbiology and Hygiene, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Elfriede-Aulhorn-Straße 5, 72076 Tübingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolz
authors.affiliation: Department of Microbial Genetics, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.affiliation: Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.|German Center for Infection Research, University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kretschmer
authors.affiliation: Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.|German Center for Infection Research, University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000473:pathology; D055666:Lipopeptides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D010636:Phenols; D018805:Sepsis / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D012995:Solubility; D013211:Staphylococcus aureus / Q000472:pathogenicity; D013501:Surface-Active Agents / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D055666:Lipopeptides; D010636:Phenols; D013501:Surface-Active Agents; D051195:Toll-Like Receptor 2