title: The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing.
abstract: Interleukin-8 (IL-8) promotes neutrophil-mediated host defense through its chemoattractant and immunostimulatory activities. The Group A Streptococcus (GAS) protease SpyCEP (also called ScpC) cleaves IL-8, and SpyCEP expression is strongly upregulated in vivo in the M1T1 GAS strains associated with life-threatening systemic disease including necrotizing fasciitis. Coupling allelic replacement with heterologous gene expression, we show that SpyCEP is necessary and sufficient for IL-8 degradation. SpyCEP decreased IL-8-dependent neutrophil endothelial transmigration and bacterial killing, the latter by reducing neutrophil extracellular trap formation. The knockout mutant lacking SpyCEP was attenuated for virulence in murine infection models, and SpyCEP expression conferred protection to coinfecting bacteria. We also show that the zoonotic pathogen Streptococcus iniae possesses a functional homolog of SpyCEP (CepI) that cleaves IL-8, promotes neutrophil resistance, and contributes to virulence. By inactivating the multifunctional host defense peptide IL-8, the SpyCEP protease impairs neutrophil clearance mechanisms, contributing to the pathogenesis of invasive streptococcal infection.
authors.affiliation: Department of Pediatrics, Division of Pharmacology & Drug Discovery, La Jolla, CA 92093, USA.
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.forename: Anjuli M
authors.initials: AM
authors.lastname: Timmer
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Pence
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Locke
authors.forename: John T
authors.initials: JT
authors.lastname: Buchanan
authors.forename: Claire E
authors.initials: CE
authors.lastname: Turner
authors.forename: Inbal
authors.initials: I
authors.lastname: Mishalian
authors.forename: Shiranee
authors.initials: S
authors.lastname: Sriskandan
authors.forename: Emanuel
authors.initials: E
authors.lastname: Hanski
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000382:microbiology; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology; D013291:Streptococcus / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000235:genetics; D014774:Virulence
chemical_list: D016209:Interleukin-8; D010447:Peptide Hydrolases; C527349:SpyCEP protein, Streptococcus pyogenes