Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes

PLoS Pathogens

Christian W. Remmele¹  Marcus Dittrich¹  Christina Schuelein-Voelk¹  Martin J. Fraunholz²  Sudip Das²  Sebastian Blättner²  Kerstin Paprotka²  Markus Krischke³  Bruno Huettel³  Tobias Hertlein⁴  Ursula Eilers⁴  Dorothee Kretschmer⁵  Thomas Rudel⁶  Martin J. Mueller⁶  Tobias Müller⁷  Knut Ohlsen⁸  Richard Reinhardt⁸ 

[1] Biocenter, Chair of Bioinformatics, University of Würzburg, Würzburg, Germany;Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany;Biocenter, Chair of Pharmaceutical Biology, University of Würzburg, Würzburg, Germany;Core Unit Functional Genomics, University of Würzburg, Würzburg, Germany;Department of Infection Biology, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University Tübingen, Tübingen, Germany;Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany;Institute of Human Genetics, University of Würzburg, Würzburg, Germany;Max Planck Genome Centre, Cologne, Germany

关键词: Staphylococcus aureus;    Host cells;    Neutrophils;    Macrophages;    Cell death;    Transposable elements;    Cytotoxicity;    Epithelial cells;   

DOI  :  10.1371/journal.ppat.1005857

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection.

【 授权许可】

CC BY