Formyl-peptide receptor and phagocytosis–How does S. aureus use Formyl-peptide receptor 2 for its own purposes?

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Formyl peptide receptors (FPRs) represent important pattern recognition receptors. They are highly expressed on neutrophils and monocytes. Their activation leads to migration of leukocytes to the infection site and to the release of reactive oxygen species (ROS). FPR1 senses short formylated peptides released by all kinds of bacteria, whereas FPR2 is activated by phenol-soluble modulin (PSM) peptides from Staphylococcus aureus. As neutrophils belong to the first cells reaching the infection focus, we investigated whether FPRs do also influence the phagocytic capacity of these cells. Our preliminary data show that simultaneous stimulation of neutrophils with FPR ligands and bacteria during phagocytosis leads to a significant increase of engulfed S. aureus. We observed that this effect depends on FPR mediated upregulation of complement receptors and of the FC receptor. However, we observed that increased phagocytosis does not necessarily lead to a better killing of S. aureus. Therefore, we hypothesized that activation of FPR1 and FPR2 by bacteria leads to increased phagocytosis of bacteria. We assume that only bacteria that cannot escape from the phagosome can be effectively killed from neutrophils. We will elucidate, if FPR2 is also involved in phagosomal escape of S. aureus. Since S. aureus uses PSMs also for intracellular survival, we suppose that S. aureus induces its phagocytosis willingly via FPR2 activation. Interestingly, it has been shown that many of the secreted leucocidins of S. aureus induce their toxic potential only via binding to various complement or chemokine receptors. We wanted to know, if up- or downregulation of complement or chemokine receptors through FPR activation leads to modified capacity of leucocidins to lyse neutrophils. Furthermore, we will investigate using a mouse peritonitis model, if the loss of Fpr2 influence phagocytosis of a various leucocidin deficient S. aureus strains.