Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus.
Virulence of emerging community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and other highly pathogenic S. aureus strains depends on their production of 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 unclear. Here, 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 severely diminished neutrophil detection of CA-MRSA. Furthermore, a specific inhibitor of FPR2/ALX and of its functional mouse counterpart blocked PSM-mediated leukocyte infiltration in vivo in a mouse model. Thus, the innate immune system uses a distinct FPR2/ALX-dependent mechanism to specifically sense bacterial peptide toxins and detect highly virulent bacterial pathogens. FPR2/ALX represents an attractive target for new anti-infective or anti-inflammatory strategies.
Kretschmer
Dorothee
D
Cellular and Molecular Microbiology Division, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfriede-Aulhorn-Strasse 6, 72076 Tübingen, Germany.
Gleske
Anne-Kathrin
AK
Rautenberg
Maren
M
Wang
Rong
R
Köberle
Martin
M
Bohn
Erwin
E
Schöneberg
Torsten
T
Rabiet
Marie-Joséphe
MJ
Boulay
Francois
F
Klebanoff
Seymour J
SJ
van Kessel
Kok A
KA
van Strijp
Jos A
JA
Otto
Michael
M
Peschel
Andreas
A
D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D017714:Community-Acquired Infections / Q000382:microbiology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000302:isolation & purification / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D011485:Protein Binding; D044042:Receptors, Formyl Peptide / Q000378:metabolism* / Q000502:physiology; D044067:Receptors, Lipoxin / Q000378:metabolism*; D013203:Staphylococcal Infections
D001427:Bacterial Toxins; C105101:FPR2 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; C025971:staphylococcal delta toxin