A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues.
Group A Streptococcus (GAS) causes the life-threatening infection in humans known as necrotizing fasciitis (NF). Infected subcutaneous tissues from an NF patient and mice challenged with the same GAS strain possessed high bacterial loads but a striking paucity of infiltrating polymorphonuclear leukocytes (PMNs). Impaired PMN recruitment was attributed to degradation of the chemokine IL-8 by a GAS serine peptidase. Here, we use bioinformatics approach coupled with target mutagenesis to identify this peptidase as ScpC. We show that SilCR pheromone downregulates scpC transcription via the two-component system-SilA/B. In addition, we demonstrate that in vitro, ScpC degrades the CXC chemokines: IL-8 (human), KC, and MIP-2 (both murine). Furthermore, using a murine model of human NF, we demonstrate that ScpC, but not the C5a peptidase ScpA, is an essential virulence factor. An ScpC-deficient mutant is innocuous for untreated mice but lethal for PMN-depleted mice. ScpC degrades KC and MIP-2 locally in the infected skin tissues, inhibiting PMN recruitment. In conclusion, ScpC represents a novel GAS virulence factor functioning to directly inactivate a key element of the host innate immune response.
Hidalgo-Grass
Carlos
C
Institute of Microbiology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Mishalian
Inbal
I
Dan-Goor
Mary
M
Belotserkovsky
Ilia
I
Eran
Yoni
Y
Nizet
Victor
V
Peled
Amnon
A
Hanski
Emanuel
E
D018829:Adhesins, Bacterial / Q000378:metabolism*; D000818:Animals; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000382:microbiology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000382:microbiology* / Q000473:pathology; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000472:pathogenicity; D014158:Transcription, Genetic; D014774:Virulence
D018829:Adhesins, Bacterial; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D015846:Monokines; D012333:RNA, Messenger; D010450:Endopeptidases; D012697:Serine Endopeptidases; C053088:C5a peptidase