title: Streptococcus pyogenes M49 plasminogen/plasmin binding facilitates keratinocyte invasion via integrin-integrin-linked kinase (ILK) pathways and protects from macrophage killing.
abstract: The entry into epithelial cells and the prevention of primary immune responses are a prerequisite for a successful colonization and subsequent infection of the human host by Streptococcus pyogenes (group A streptococci, GAS). Here, we demonstrate that interaction of GAS with plasminogen promotes an integrin-mediated internalization of the bacteria into keratinocytes, which is independent from the serine protease activity of potentially generated plasmin. α(1)β(1)- and α(5)β(1)-integrins were identified as the major keratinocyte receptors involved in this process. Inhibition of integrin-linked kinase (ILK) expression by siRNA silencing or blocking of PI3K and Akt with specific inhibitors, reduced the GAS M49-plasminogen/plasmin-mediated invasion of keratinocytes. In addition, blocking of actin polymerization significantly reduced GAS internalization into keratinocytes. Altogether, these results provide a first model of plasminogen-mediated GAS invasion into keratinocytes. Furthermore, we demonstrate that plasminogen binding protects the bacteria against macrophage killing.
authors.affiliation: Institute of Medical Microbiology, Virology and Hygiene, Rostock University Hospital, Schillingallee 70, 18057 Rostock, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Siemens
authors.forename: Nadja
authors.initials: N
authors.lastname: Patenge
authors.forename: Juliane
authors.initials: J
authors.lastname: Otto
authors.forename: Tomas
authors.initials: T
authors.lastname: Fiedler
authors.forename: Bernd
authors.initials: B
authors.lastname: Kreikemeyer
mesh_terms: D001430:Bacteriocins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D008954:Models, Biological; D008957:Models, Genetic; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000378:metabolism*; D000099200:Scaffold Protein ILK
chemical_list: D001430:Bacteriocins; D005341:Fibrinolysin; D039222:Integrin alpha1beta1; D039081:Integrin alpha5beta1; D016023:Integrins; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C090833:streptococcin A M49 protein, Streptococcus