Immune modulation by molecules of Staphylococcus aureus

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Dokumentart: Dissertation
Date: 2022-05-22
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Peschel, Andreas (Prof. Dr.)
Day of Oral Examination: 2020-05-22
DDC Classifikation: 500 - Natural sciences and mathematics
Keywords: Staphylococcus aureus , Immunsystem
License: Publishing license excluding print on demand
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Dissertation ist gesperrt bis 22. Mai 2022 !


Staphylococcus aureus, a major human pathogen, is the source or various infections ranging from mild skin abscesses to severe endocarditis and sepsis. The pathogenesis of S. aureus is based on the production of a wide variety of toxins and immune modulators, which can support bacterial immune evasion but also immune activation. For example, S. aureus releases the cytolytic phenol-soluble modulins (PSMs), which impair leukocyte membrane integrity, activate the human formyl-peptide receptor 2 (FPR2) and influence the release of immune-stimulatory lipoproteins (Lpps). Lpps are membrane-anchored proteins that are abundant in the S. aureus secretome although they lack a specific release system. We observed here that S. aureus membrane vesicles (MVs) contain Lpps and represent a vehicle for Lpp release. MV formation was strongly enhanced by an external turgor pressure as well as the presence of the surfactant-like PSMs, which enhanced membrane fluidity. The immune stimulatory component of Lpps is the lipid-anchor, by which Lpps are anchored in MVs. For an effective Toll-like receptor 2 (TLR2) activation, this lipid anchor has to be liberated. We could demonstrate that increasing PSM concentrations induces MV disruption and thus the release of Lpps, PSMs and other MV-associated proteins, which induce TLR2 and FPR2 activation, respectively. However, also bacterial metabolites can interact with the human immune system. Short carboxylic acids with less than six carbon atoms are the major products of bacterial fermentation or the phosphotransacetylase-acetate kinase (Pta-AckA) pathway. This group of molecules is referred to as short chain fatty acids (SCFAs) and have been described to activate the neutrophilic free-fatty acid receptor GPR43 (FFAR2). Here we could show that GPR43 activation by the SCFA member acetate transferred neutrophils into a primed state, which is characterized by an increased immune reaction towards subsequent bacterial stimulation. GPR43-dependent priming led, after restimulation with activating ligands, to increased chemotaxis and cytokine / ROS release. Furthermore, priming via GPR43 resulted in enhanced expression of Fc- and complement receptors and in improved bacterial elimination. This acetate-dependent priming was also observed in an in vivo murine sepsis model, where a GPR43-mediated priming resulted in drastically reduced bacterial loads and disease severity. In summary, in the first part we could show that S. aureus releases TLR2-activating Lpps through PSM- and turgor-driven MV-release. And in the second part we demonstrated that acetate activates neutrophils in a GPR43-dependent manner and thereby enhances the immune reaction against S. aureus.

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