Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis

• Published in: The EMBO journal Vol. 31; no. 17; pp. 3607 - 3619
• Main Authors: Laarman, Alexander J, Mijnheer, Gerdien, Mootz, Joe M, van Rooijen, Willemien J M, Ruyken, Maartje, Malone, Cheryl L, Heezius, Erik C, Ward, Richard, Milligan, Graeme, van Strijp, Jos A G, de Haas, Carla J C, Horswill, Alexander R, van Kessel, Kok P M, Rooijakkers, Suzan H M
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 29.08.2012; Nature Publishing Group UK; Springer Nature B.V; Nature Publishing Group
• Subjects: Animals; Bacterial Proteins - immunology; Cells, Cultured; Chemotaxis, Leukocyte - immunology; CXCR2; Cysteine Endopeptidases - immunology; EMBO19; EMBO23; Female; HEK293 Cells; Humans; immune evasion; Immune system; Immunology; Mice; Mice, Inbred C57BL; Microbiology; Molecular biology; Neutrophil Activation - immunology; Neutrophil Infiltration - immunology; Neutrophils - immunology; Pathogens; Proteases; Proteinase inhibitors; Proteins; Receptors, Interleukin-8B - antagonists & inhibitors; Receptors, Interleukin-8B - immunology; Staphylococcus aureus; Staphylococcus infections; U937 Cells; immune evasion; CXCR2; proteases
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2012.212

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. Neutrophil activation and recruitment to the site of infection are critical for host immunity. In humans, the cysteine protease Staphopain A of the pathogen S. aureus blocks this process by cleaving the chemokine receptor CXCR2.