Staphylococcus aureus exploits cathelicidin antimicrobial peptides produced during early pneumonia to promote staphylokinase-dependent fibrinolysis.
The increasing prevalence of Staphylococcus aureus strains isolated from hospital- and community-acquired respiratory tract infections is an important public health concern worldwide. The majority of S. aureus strains produce staphylokinase, a plasminogen activator capable of inactivating neutrophil alpha-defensins and of impairing phagocytosis via opsonin degradation. Cathelicidin antimicrobial peptides are present at sites of infection before the release of neutrophil alpha-defensins. Therefore, we hypothesized that staphylokinase interacts with cathelicidin during the early pathogenesis of S. aureus airway infection. In a mouse intranasal infection model, cathelicidin was strongly up-regulated in the airways during the development of staphylococcal pneumonia. In vitro, cathelicidin bound directly to staphylokinase and augmented staphylokinase-dependent plasminogen activation and fibrinolysis at concentrations consistent with those detected in the airways during infection. These data suggest that staphylokinase production may be a novel virulence mechanism by which S. aureus exploits cathelicidin to promote fibrinolysis, leading to enhanced bacterial dissemination and invasive infection.
Braff
Marissa H
MH
Division of Infectious Disease, Children's Hospital and Regional Medical Center, University of Washington, Seattle, WA 98109, USA.
Jones
Amanda L
AL
Skerrett
Shawn J
SJ
Rubens
Craig E
CE
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D018893:Bronchoalveolar Lavage; D054804:Cathelicidins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis; D008666:Metalloendopeptidases / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000494:pharmacology; D011023:Pneumonia, Staphylococcal / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000201:enzymology / Q000378:metabolism* / Q000472:pathogenicity
D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D054804:Cathelicidins; D010960:Plasminogen Activators; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus