The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing.
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.
Zinkernagel
Annelies S
AS
Department of Pediatrics, Division of Pharmacology & Drug Discovery, La Jolla, CA 92093, USA.
Timmer
Anjuli M
AM
Pence
Morgan A
MA
Locke
Jeffrey B
JB
Buchanan
John T
JT
Turner
Claire E
CE
Mishalian
Inbal
I
Sriskandan
Shiranee
S
Hanski
Emanuel
E
Nizet
Victor
V
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
D016209:Interleukin-8; D010447:Peptide Hydrolases; C527349:SpyCEP protein, Streptococcus pyogenes