title: Plasminogen activation by staphylokinase enhances local spreading of S. aureus in skin infections.
abstract: BACKGROUND
  Staphylococcus 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.
  
  
  RESULTS
  SAK-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.
  
  
  CONCLUSIONS
  SAK contributes to the phenotype of S. aureus skin infections by enhancing bacterial spreading as a result of fibrinolytic and proteolytic activation.
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. marijke.peetermans@med.kuleuven.be.
authors.forename: Marijke
authors.initials: M
authors.lastname: Peetermans
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. thomas.vanassche@med.kuleuven.be.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanassche
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. laurens.liesenborghs@med.kuleuven.be.
authors.forename: Laurens
authors.initials: L
authors.lastname: Liesenborghs
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. jorien.claes@med.kuleuven.be.
authors.forename: Jorien
authors.initials: J
authors.lastname: Claes
authors.affiliation: Biomedical MRI/Molecular Small Animal Imaging Center, KU Leuven, Herestraat 49, Box 505, Leuven, Belgium. greetje.vandevelde@med.kuleuven.be.
authors.forename: Greetje
authors.initials: G
authors.lastname: Vande Velde
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Gothenburg, Guldhedsgatan 10, Box 480, Gothenburg, Sweden. jakub.kwiecinski@rheuma.gu.se.
authors.forename: Jakub
authors.initials: J
authors.lastname: Kwiecinksi
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Gothenburg, Guldhedsgatan 10, Box 480, Gothenburg, Sweden. tao.jin@rheuma.gu.se.
authors.forename: Tao
authors.initials: T
authors.lastname: Jin
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. bart.degeest@med.kuleuven.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. marc.hoylaerts@med.kuleuven.be.
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. roger.lijnen@med.kuleuven.be.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Lijnen
authors.affiliation: Center for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Box 911, Leuven, Belgium. peter.verhamme@med.kuleuven.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D008666:Metalloendopeptidases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010958:Plasminogen / Q000378:metabolism*; D012867:Skin / Q000382:microbiology* / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000382:microbiology* / Q000473:pathology; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000502:physiology
chemical_list: D010958:Plasminogen; D005341:Fibrinolysin; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus