Human Formyl Peptide Receptor 2 Senses Highly Pathogenic Staphylococcus aureus

Abstract

SUMMARY Virulence of the emerging Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) and other highly pathogenic S. aureus depends on the recently discovered phenol-soluble modulin (PSM) peptide toxins, which combine the capacities to attract and lyse neutrophils. The molecular basis of PSM-stimulated neutrophil recruitment has remained unknown. We demonstrate that the human formyl peptide receptor 2 (FPR2/ALX), which has previously been implicated in control of endogenous inflammatory processes, senses PSMs at nanomolar concentrations and initiates proinflammatory neutrophil responses to CA-MRSA. Specific blocking of FPR2/ALX or deletion of PSM genes in CA-MRSA led to severely diminished capacities of neutrophils to detect CA-MRSA. A specific inhibitor of FPR2/ALX and its functional mouse counterpart blocked PSM-mediated leukocyte infiltration in vivo in a mouse model. Thus, the innate immune system uses a new FPR2/ALX-dependent mechanism to sense bacterial peptide toxins and detect highly virulent bacterial pathogens. FPR2/ALX represents an attractive target for new anti-infective or anti-inflammatory strategies.

Structural Characterization and Inhibitory Profile of Formyl Peptide Receptor 2 Selective Peptides Descending from a PIP2-Binding Domain of Gelsolin

“…High-affinity formyl peptides for FPR1 have been found in both Escherichia coli (fMLF) and S. aureus (fMIFL), and neither of these peptides interacts with FPR2 (41,42); accordingly, we found the neutrophil response to these agonists to be insensitive to PBP10. We also found that PBP10 completely abolished the neutrophil response induced by two newly described formyl peptides derived from S. aureus exerting high binding affinity for FPR2 (12). Apparently, the presence of a formyl group does not play a significant role in mediating receptor specificity between FPR1 and FPR2 (43).…”

“…flammatory mediators (9,12,29,32,33). Although the two receptors share large sequence similarities and induce almost identical cellular responses, there is one fundamental difference in their downstream signaling; that is, the FPR2 signaling is PBP10 sensitive, whereas the FPR1 signaling is PBP10 insensitive (16,17).…”

“…The biological significance of FPR1 in host defense has recently been clearly elucidated by the facts that 1) mice deficient in Fpr1 (the murine ortholog of FPR1) are susceptible to bacterial infections, and that 2) mitochondria-derived FPR1 agonists constitute the basis for the trauma reaction in patients suffering from the severe systemic inflammatory response syndrome, a state that clinically very much resembles a septic infection (10). With respect to FPR2, the other neutrophil receptor, a great number of nonformylated molecules, including the lipoxins and recently also a group of formylated agonists, have been described, but no defined structure has yet been identified as the determinant for binding and activation (9,11,12). Our knowledge about the biological functions of FPR2 is also fairly limited, but recent studies demonstrate important roles for the receptor in dampening as well as amplifying inflammation (13,14).…”

Staphylococcus aureus toxins – Their functions and genetics

“…2009;Cheung, Rigby et al 2010). This response is mediated by activation of the 29 human formyl peptide receptor 2 (FPR2) (Kretschmer, Gleske et al 2010). Thirdly,…”

Studying Interactions of <em>Staphylococcus aureus</em> with Neutrophils by Flow Cytometry and Time Lapse Microscopy

“…Excessive phenol soluble modulin (PSMs) production of CA-MRSA has been associated with higher virulence 4,5 . Human neutrophils can recognize these PSMs via FPR2 which lead to activation of this G-protein coupled receptor 6 . One of the earliest events is the mobilization of intracellular stores of calcium (Ca 2+ ).…”