title: Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors.
abstract: Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomolar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity.
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors.forename: Daphne A C
authors.initials: DA
authors.lastname: Stapels
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506;
authors.forename: Kasra X
authors.initials: KX
authors.lastname: Ramyar
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University Faculty of Medicine and Medical Center, D-66421 Homburg/Saar, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine, D-30559 Hannover, Germany; and.
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors.forename: Fin J
authors.initials: FJ
authors.lastname: Milder
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors.forename: Maartje
authors.initials: M
authors.lastname: Ruyken
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University Faculty of Medicine and Medical Center, D-66421 Homburg/Saar, Germany;
authors.forename: Janina
authors.initials: J
authors.lastname: Eisenbeis
authors.affiliation: School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110.
authors.forename: William J
authors.initials: WJ
authors.lastname: McWhorter
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University Faculty of Medicine and Medical Center, D-66421 Homburg/Saar, Germany;
authors.forename: Mathias
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors.forename: Kok P M
authors.initials: KP
authors.lastname: van Kessel
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506;
authors.forename: Brian V
authors.initials: BV
authors.lastname: Geisbrecht
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands; s.h.m.rooijakkers@umcutrecht.nl.
authors.forename: Suzan H M
authors.initials: SH
authors.lastname: Rooijakkers
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000378:metabolism; D055162:Biocatalysis; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009504:Neutrophils / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000473:pathology; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase
keywords: bacteria; immune evasion; phagocytes