Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes.
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 intrac...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-09-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5025175?pdf=render |
| _version_ | 1818008371913031680 |
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| author | Sebastian Blättner Sudip Das Kerstin Paprotka Ursula Eilers Markus Krischke Dorothee Kretschmer Christian W Remmele Marcus Dittrich Tobias Müller Christina Schuelein-Voelk Tobias Hertlein Martin J Mueller Bruno Huettel Richard Reinhardt Knut Ohlsen Thomas Rudel Martin J Fraunholz |
| author_facet | Sebastian Blättner Sudip Das Kerstin Paprotka Ursula Eilers Markus Krischke Dorothee Kretschmer Christian W Remmele Marcus Dittrich Tobias Müller Christina Schuelein-Voelk Tobias Hertlein Martin J Mueller Bruno Huettel Richard Reinhardt Knut Ohlsen Thomas Rudel Martin J Fraunholz |
| author_sort | Sebastian Blättner |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T05:28:26Z |
| format | Article |
| id | doaj.art-9698c7667459459cb09fc76121b08fa8 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-14T05:28:26Z |
| publishDate | 2016-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-9698c7667459459cb09fc76121b08fa82022-12-22T02:09:53ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-09-01129e100585710.1371/journal.ppat.1005857Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes.Sebastian BlättnerSudip DasKerstin PaprotkaUrsula EilersMarkus KrischkeDorothee KretschmerChristian W RemmeleMarcus DittrichTobias MüllerChristina Schuelein-VoelkTobias HertleinMartin J MuellerBruno HuettelRichard ReinhardtKnut OhlsenThomas RudelMartin J FraunholzCommunity-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.http://europepmc.org/articles/PMC5025175?pdf=render |
| spellingShingle | Sebastian Blättner Sudip Das Kerstin Paprotka Ursula Eilers Markus Krischke Dorothee Kretschmer Christian W Remmele Marcus Dittrich Tobias Müller Christina Schuelein-Voelk Tobias Hertlein Martin J Mueller Bruno Huettel Richard Reinhardt Knut Ohlsen Thomas Rudel Martin J Fraunholz Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes. PLoS Pathogens |
| title | Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes. |
| title_full | Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes. |
| title_fullStr | Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes. |
| title_full_unstemmed | Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes. |
| title_short | Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes. |
| title_sort | staphylococcus aureus exploits a non ribosomal cyclic dipeptide to modulate survival within epithelial cells and phagocytes |
| url | http://europepmc.org/articles/PMC5025175?pdf=render |
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