Abstract
BackgroundStaphylococcus aureus (S. aureus) is a frequent cause of skin and soft tissue infections. A unique feature of S. aureus is the combined presence of coagulases that trigger fibrin formation and of the plasminogen activator staphylokinase (SAK). Whereas the importance of fibrin generation for S. aureus virulence has been established, the role of SAK remains unclear.We studied the role of plasminogen activation by SAK in a skin infection model in mice and evaluated the impact of alpha-2-antiplasmin (α2AP) deficiency on the spreading and proteolytic activity of S. aureus skin infections. The species-selectivity of SAK was overcome by adenoviral expression of human plasminogen. Bacterial spread and density was assessed non-invasively by imaging the bioluminescence of S. aureus Xen36.ResultsSAK-mediated plasmin activity increased the local invasiveness of S. aureus, leading to larger lesions with skin disruption as well as decreased bacterial clearance by the host. Even though fibrin and bacterial surfaces protected SAK-mediated plasmin activity from inhibition by α2AP, the deficiency of α2AP resulted in increased bacterial spreading. SAK-mediated plasmin also induced secondary activation of gelatinases, shown both in vitro and in lesions from the in vivo model.ConclusionSAK contributes to the phenotype of S. aureus skin infections by enhancing bacterial spreading as a result of fibrinolytic and proteolytic activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-014-0310-7) contains supplementary material, which is available to authorized users.
Highlights
Staphylococcus aureus (S. aureus) is a frequent cause of skin and soft tissue infections
Bacterial staphylokinase production Supernatant of overnight cultures of the bioluminescent S. aureus Xen36 contained similar levels of SAK compared to lab strains and to clinical S. aureus strains from skin infection and from bacteremia with cutaneous origin
Skin infection model Adenoviral-mediated human plasminogen expression To overcome the species-selectivity of SAK for huPlg, huPlg was expressed in mice through adenoviral gene transfer
Summary
Staphylococcus aureus (S. aureus) is a frequent cause of skin and soft tissue infections. Staphylococcus aureus (S. aureus) is the leading cause of skin and soft tissue infections, both community- and hospital-acquired [1,2]. We and others have shown that fibrin formation induced by the bacterial prothrombin activators staphylocoagulase and von Willebrand factor-binding protein is an important virulence factor for both localized and systemic infections by S. aureus and is essential for abscess formation [3,4,5,6]. Streptokinase, secreted by group A, C and G streptococci, is the other well-known bacterial plasminogen activator. Like SAK, streptokinase is specific for human plasminogen (huPlg) but its action is not inhibited by α2AP [11]. A subcluster of streptokinase (type 2b) has been identified that is sensitive to α2AP inhibition, leading to site-restricted plasminogen activation in these, mostly skin-trophic, group A streptococci [14]
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