TY  - JOUR
A1  - Blättner, Sebastian
A1  - Das, Sudip
A1  - Paprotka, Kerstin
A1  - Eilers, Ursula
A1  - Krischke, Markus
A1  - Kretschmer, Dorothee
A1  - Remmele, Christian W.
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Schuelein-Voelk, Christina
A1  - Hertlein, Tobias
A1  - Mueller, Martin J.
A1  - Huettel, Bruno
A1  - Reinhardt, Richard
A1  - Ohlsen, Knut
A1  - Rudel, Thomas
A1  - Fraunholz, Martin J.
T1  - Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes
JF  - PLoS Pathogens
N2  - 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.
KW  - cell death
KW  - cytotoxicity
KW  - Staphylococcus aureus
KW  - host cells
KW  - neutrophils
KW  - macrophages
KW  - transposable elements
KW  - epithelial cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180380
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Hanzelmann, Dennis
A1  - Joo, Hwang-Soo
A1  - Franz-Wachtel, Mirita
A1  - Hertlein, Tobias
A1  - Stevanovic, Stefan
A1  - Macek, Boris
A1  - Wolz, Christiane
A1  - Götz, Friedrich
A1  - Otto, Michael
A1  - Kretschmer, Dorothee
A1  - Peschel, Andreas
T1  - Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants
JF  - Nature Communications
N2  - 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.
KW  - Pathogens
KW  - Toll-like receptors
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165975
VL  - 7
ER  - 
TY  - JOUR
A1  - Selle, Martina
A1  - Hertlein, Tobias
A1  - Oesterreich, Babett
A1  - Klemm, Theresa
A1  - Kloppot, Peggy
A1  - Müller, Elke
A1  - Ehricht, Ralf
A1  - Stentzel, Sebastian
A1  - Bröker, Barbara M.
A1  - Engelmann, Susanne
A1  - Ohlsen, Knut
T1  - Global antibody response to Staphylococcus aureus live-cell vaccination
JF  - Scientific Reports
N2  - The pathogen Staphylococcus aureus causes a broad range of severe diseases and is feared for its ability to rapidly develop resistance to antibiotic substances. The increasing number of highly resistant S. aureus infections has accelerated the search for alternative treatment options to close the widening gap in anti-S. aureus therapy. This study analyses the humoral immune response to vaccination of Balb/c mice with sublethal doses of live S. aureus. The elicited antibody pattern in the sera of intravenously and intramuscularly vaccinated mice was determined using of a recently developed protein array. We observed a specific antibody response against a broad set of S. aureus antigens which was stronger following i.v. than i.m. vaccination. Intravenous but not intramuscular vaccination protected mice against an intramuscular challenge infection with a high bacterial dose. Vaccine protection was correlated with the strength of the anti-S. aureus antibody response. This study identified novel vaccine candidates by using protein microarrays as an effective tool and showed that successful vaccination against S. aureus relies on the optimal route of administration.
KW  - pathogens
KW  - bacterial infection
KW  - cell vaccines
KW  - Staphylococcus aureus
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181245
VL  - 6
ER  -