Chemokine-cleaving Streptococcus pyogenes protease SpyCEP is necessary and sufficient for bacterial dissemination within soft tissues and the respiratory tract.
SpyCEP is a Streptococcus pyogenes protease that cleaves CXCL8/IL-8 and its activity is associated with human invasive disease severity. We investigated the role of SpyCEP in S. pyogenes necrotizing fasciitis and respiratory tract infection in mice using isogenic strains differing only in SpyCEP expression. SpyCEP cleaved human CXCL1, 2, 6 and 8 plus murine CXCL1 and 2 at a structurally conserved site. Mice were infected in thigh muscle with a strain of S. pyogenes that expresses a high level of SpyCEP, or with an isogenic non-SpyCEP expressing strain. SpyCEP expression by S. pyogenes hindered bacterial clearance from muscle, and enhanced bacterial spread, associated with cleavage of murine chemoattractant CXCL1. Mice were then infected with Lactococcus lactis strains that differed only in SpyCEP expression. In contrast to the parent L. lactis strain (lacks SpyCEP), which was avirulent when administered intramuscularly, infection with a strain that expressed SpyCEP heterologously led to dramatic systemic illness within 24 h, failure to clear bacteria from muscle and marked dissemination to other organs. In the upper airways, SpyCEP expression was required for survival of L. lactis but not S. pyogenes. However, dissemination of S. pyogenes to the lung was SpyCEP-dependent and was associated with evidence of chemokine cleavage. Taken together, the studies provide clear evidence that SpyCEP is necessary and sufficient for systemic bacterial dissemination from a soft tissue focus in this model and also underlies dissemination in the respiratory tract.
Kurupati
Prathiba
P
Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Turner
Claire E
CE
Tziona
Ioanna
I
Lawrenson
Richard A
RA
Alam
Faraz M
FM
Nohadani
Mahrokh
M
Stamp
Gordon W
GW
Zinkernagel
Annelies S
AS
Nizet
Victor
V
Edwards
Robert J
RJ
Sriskandan
Shiranee
S
D000595:Amino Acid Sequence; D000818:Animals; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015169:Colony Count, Microbial; D017124:Conserved Sequence; D019115:Fasciitis, Necrotizing / Q000382:microbiology*; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D013294:Lactococcus lactis / Q000235:genetics / Q000472:pathogenicity; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008853:Microscopy; D008969:Molecular Sequence Data; D009132:Muscles / Q000382:microbiology / Q000473:pathology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000382:microbiology*; D016415:Sequence Alignment; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D037521:Virulence Factors; D010447:Peptide Hydrolases; C527349:SpyCEP protein, Streptococcus pyogenes