Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants

Dennis Hanzelmann, Hwang-Soo Joo, Mirita Franz-Wachtel, Tobias Hertlein, Stefan Stevanovic, Boris Macek, Christiane Wolz, Friedrich Götz, Michael Otto, Dorothee Kretschmer () and Andreas Peschel
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Dennis Hanzelmann: Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen
Hwang-Soo Joo: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Mirita Franz-Wachtel: Proteome Center Tübingen, Interfaculty Institute of Cell Biology, University of Tübingen
Tobias Hertlein: Institute for Molecular Infection Biology, University of Würzburg
Stefan Stevanovic: Interfaculty Institute for Cell Biology, Eberhard Karls University
Boris Macek: Proteome Center Tübingen, Interfaculty Institute of Cell Biology, University of Tübingen
Christiane Wolz: Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen
Friedrich Götz: Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen
Michael Otto: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Dorothee Kretschmer: Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen
Andreas Peschel: Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12304

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