Rolle der Formyl-Peptid Rezeptoren in der Phagozytose und wie Staphylococcus aureus den Formyl-Peptid Rezeptor 2 für seinen eigenen Vorteil nutzt.
Immunologie
Zusammenfassung der Projektergebnisse
The human formyl-peptide receptors (FPR) were primarily described as myeloid cell receptors, as they are strongly expressed in neutrophils (PMNs) (FPR1, FPR2) and monocytes (FPR1, FPR2 and FPR3). In addition to myeloid cells, we showed recently that FPR1 and FPR2 are also expressed in keratinocytes, the primary cell type of the outermost layer of the skin. FPR1 preferentially recognizes short peptides of approximately 3-5 amino acids that start with N-formyl-methionine, whereas FPR2 is activated preferentially by longer peptides with α-helical, amphipathic properties. The best-known bacterial ligands of FPR2 are the phenol soluble modulins (PSMs), staphylococcus-derived toxins that can disrupt cellular and phagosomal membrane integrity at high concentrations. We found that FPR activation enhances phagocytosis of Staphylococcus aureus by PMNs, which was difficult to reconcile with the fact that increased phagocytosis does not lead to increased killing in in vivo models of infection. Thus, we hypothesized that activation of FPR1 and FPR2 by bacteria leads to increased bacterial phagocytosis and killing only if bacteria cannot escape from the phagosome. We showed that the neutrophil serine proteases (NSPs) effectively degrade PSMs. However, S. aureus, but not Staphylococcus epidermidis, secretes potent NSP-inhibitory proteins, Eap, EapH1, EapH2, which prevent the degradation of PSMs by NSPs. Protecting PSMs during infection represents an important survival strategy of S. aureus. Furthermore, it has been shown that secreted toxins of S. aureus other than PSMs, so called leucocidins, exert their toxic activity only by binding to various complement or chemokine receptors. Indeed, we found exposure to FPR ligands to upregulate different complement and antibody (Fc) receptors and downregulate the chemokine receptors C5aR and CXCR1 in PMNs. Upregulation of the complement receptor CD11b by FPR1 and FPR2 ligands is known to enhance the capacity of the S. aureus LukAB leucocidin to lyse PMNs. To analyze the influence of FPR activation on the activity of further bicomponent leucocidins, we infected human PMNs with either opsonized or non-opsonized S. aureus strains carrying transposoninsertions in different leucocidin genes and determined their ability to lyse leukocytes. As the USA300∆hlgA-mutant proved to be slightly more sensitive to normal human serum (NHS)-opsonization, we concluded that the bicomponent leucocidin HlgAB, which binds to the chemokine receptors CXCR1, CXCR2 and CCR2, could play a role in phagosomal escape. However, whether downregulation of C5aR and CXCR1 by FPR ligands receptor prevents cytotoxicity must be analyzed in the future. Since the funding period overlapped with the coronavirus pandemic, we could not perform all the planned experiments. In addition to formylated peptides, most bacteria release short-chain fatty acids (SCFA), e.g., acetate. Innate immune cells can use another member of the GPCR family, the free-fatty-acid receptor 2 (FFAR2), to detect acetate and thereby perceive infections. We observed that acetate prime PMNs in a GPR43-dependent manner and improves the capacity of PMNs to eliminate methicillin-resistant Staphylococcus aureus. Notably, acetate treatment rescued wild-type but not GPR43-/- mice from severe S. aureus sepsis. Acetate treatment improved the sepsis course even when applied after onset of the infection, which makes GPR43 a potential target for sepsis therapy. Therapeutic interventions based on GPR43 stimulation could become valuable strategies for reducing sepsis-associated morbidity and mortality.
Projektbezogene Publikationen (Auswahl)
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Acetate sensing by GPR43 alarms neutrophils and protects from severe sepsis. Communications Biology, 4(1).
Schlatterer, Katja; Beck, Christian; Schoppmeier, Ulrich; Peschel, Andreas & Kretschmer, Dorothee
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Short-Chain Fatty Acid and FFAR2 Activation – A New Option for Treating Infections?. Frontiers in Cellular and Infection Microbiology, 11.
Schlatterer, Katja; Peschel, Andreas & Kretschmer, Dorothee
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Staphylococcus aureus Depends on Eap Proteins for Preventing Degradation of Its Phenol-Soluble Modulin Toxins by Neutrophil Serine Proteases. Frontiers in Immunology, 12.
Kretschmer, Dorothee; Breitmeyer, Ricarda; Gekeler, Cordula; Lebtig, Marco; Schlatterer, Katja; Nega, Mulugeta; Stahl, Mark; Stapels, Daphne; Rooijakkers, Suzan & Peschel, Andreas
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Keratinocytes use FPR2 to detect Staphylococcus aureus and initiate antimicrobial skin defense. Frontiers in Immunology, 14.
Lebtig, Marco; Scheurer, Jasmin; Muenkel, Marie; Becker, Janna; Bastounis, Effie; Peschel, Andreas & Kretschmer, Dorothee
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The epidermal lipid barrier in microbiome–skin interaction. Trends in Microbiology, 31(7), 723-734.
Kengmo, Tchoupa Arnaud; Kretschmer, Dorothee; Schittek, Birgit & Peschel, Andreas
