Modulation of dendritic cell functions by Staphylococcus aureus phenol-soluble modulin peptides

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dc.contributor.advisor Autenrieth, Stella (Dr.)
dc.contributor.author Armbruster, Nicole
dc.date.accessioned 2017-02-07T10:02:19Z
dc.date.available 2017-02-07T10:02:19Z
dc.date.issued 2017
dc.identifier.other 48320305X de_DE
dc.identifier.uri http://hdl.handle.net/10900/74274
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-742745 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-15679
dc.description.abstract Staphylococcus aureus (S. aureus) is an important human pathogen that causes severe diseases ranging from local to systemic infections. Community-associated methicillin-resistant S. aureus (CA-MRSA) strains are highly resistant to antibiotic treatment and are the most dangerous and pathogenic strains due to their secretion of a variety of virulence factors, enabling efficient evasion of the host immune response. Phenol-soluble modulin (PSM) peptides comprise one group of secreted virulence factors that contribute to the pathogenicity of CA-MRSA. These peptides modulate various types of immune cells, including dendritic cells (DCs), which are a class of professional antigen-presenting cells that link innate and adaptive immunity. Our group previously showed that PSMs in combination with a TLR2 ligand induce tolerogenic DCs, as identified by diminished clathrin-mediated endocytosis and a modulated cytokine secretion profile characterized by anti-inflammatory IL-10, ultimately leading to impaired T cell differentiation. PSMs induce regulatory T cell (Treg) priming by DCs and, in contrast, inhibit T helper 1 cell development. However, the underlying molecular mechanisms remained elusive. Within this work, we addressed the following questions: (1) Which signaling pathways are modulated by PSMs leading to the increased production of IL-10 by DCs upon TLR2 ligand treatment? (2) Are the activated signaling pathways involved in the priming of Tregs by PSM-treated DCs? (3) Are PSMs actively internalized by DCs or are they acting by binding to the formyl-peptide receptor 2 (FPR2)? (4) Do PSMs in general affect DC functions, including maturation, cytokine production and T cell priming, upon treatment with various TLR ligands? (1) In this study, we demonstrated that mouse bone marrow-derived DCs stimulated with PSMα3 and S. aureus cell lysate (a TLR2 ligand) had increased levels of phosphorylated ERK, p38, CREB and NF-κB. However, only the inhibition of phosphorylated p38 and downstream MSK1 prevented the secretion of IL-10 in a concentration-dependent manner. (2) In DCs, the PSM-modulated p38-CREB pathway was also responsible for the altered differentiation of T cells. Inhibition of this axis also prevented the increased priming of Tregs by PSM- and TLR2-treated DCs. (3) PSMα3 peptides modulated the p38-CREB signaling pathway independent of their receptor FPR2. PSMα peptides penetrate DCs independent of macropinocytosis or receptor-mediated endocytosis, most likely through transient pore formation in the DC membrane. Furthermore, we observed that PSMα peptides co-localized with p38 as well as phosphorylated p38 in the cytosol of DCs. (4) PSM peptides induced a tolerogenic DC phenotype independent of the activated TLR receptor. The tolerogenic phenotyp was characterized by reduced production of the pro-inflammatory cytokines IL-12, TNF and IL-6 but increased IL-10. Moreover, the tolerogenic DCs displayed increased co-stimulatory molecule expression and an enhanced activation of Tregs by stimulation of extracellular as well as intracellular TLRs. The new scientific knowledge gained in this thesis describing the ability of secreted S. aureus PSMs to induce tolerogenic DCs by direct modulation of the p38 MAPK contributes to basic insights into the immune evasion strategies of S. aureus and to the development of possible therapeutic strategies against CA-MRSA infections in the future. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification Staphylococcus aureus de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 570 de_DE
dc.subject.other dendritic cells en
dc.subject.other phenol-soluble modulin peptides en
dc.subject.other p38 en
dc.title Modulation of dendritic cell functions by Staphylococcus aureus phenol-soluble modulin peptides en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2017-01-31
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.source erschienen in : The Journal of Immunology , 2016 Feb 1; 196(3): 1284-92 und Int J Med Microbiol. 2016 Sep 3. de_DE

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