title: Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis.
abstract: The CXC chemokine receptor 2 (CXCR2) on neutrophils, which recognizes chemokines produced at the site of infection, plays an important role in antimicrobial host defenses such as neutrophil activation and chemotaxis. Staphylococcus aureus is a successful human pathogen secreting a number of proteolytic enzymes, but their influence on the host immune system is not well understood. Here, we identify the cysteine protease Staphopain A as a chemokine receptor blocker. Neutrophils treated with Staphopain A are unresponsive to activation by all unique CXCR2 chemokines due to cleavage of the N-terminal domain, which can be neutralized by specific protease inhibitors. Moreover, Staphopain A inhibits neutrophil migration towards CXCR2 chemokines. By comparing a methicillin-resistant S. aureus (MRSA) strain with an isogenic Staphopain A mutant, we demonstrate that Staphopain A is the only secreted protease with activity towards CXCR2. Although the inability to cleave murine CXCR2 limits in-vivo studies, our data indicate that Staphopain A is an important immunomodulatory protein that blocks neutrophil recruitment by specific cleavage of the N-terminal domain of human CXCR2.
authors: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Alexander J
authors: AJ
authors: Laarman
authors: Gerdien
authors: G
authors: Mijnheer
authors: Joe M
authors: JM
authors: Mootz
authors: Willemien J M
authors: WJ
authors: van Rooijen
authors: Maartje
authors: M
authors: Ruyken
authors: Cheryl L
authors: CL
authors: Malone
authors: Erik C
authors: EC
authors: Heezius
authors: Richard
authors: R
authors: Ward
authors: Graeme
authors: G
authors: Milligan
authors: Jos A G
authors: JA
authors: van Strijp
authors: Carla J C
authors: CJ
authors: de Haas
authors: Alexander R
authors: AR
authors: Horswill
authors: Kok P M
authors: KP
authors: van Kessel
authors: Suzan H M
authors: SH
authors: Rooijakkers
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000276:immunology*; D020298:U937 Cells
chemical_list: D001426:Bacterial Proteins; D023063:Receptors, Interleukin-8B; D003546:Cysteine Endopeptidases; C501295:staphopain A protein, Staphylococcus aureus