title: Streptococcal pyogenic exotoxin B (SpeB) boosts the contact system via binding of α-1 antitrypsin.
abstract: The Streptococcus pyogenes cysteine protease SpeB (streptococcal pyrogenic exotoxin B) is important for the invasive potential of the bacteria, but its production is down-regulated following systemic infection. This prompted us to investigate if SpeB potentiated the host immune response after systemic spreading. Addition of SpeB to human plasma increased plasma-mediated bacterial killing and prolonged coagulation time through the intrinsic pathway of coagulation. This effect was independent of the enzymatic activity of SpeB and was mediated by a non-covalent medium-affinity binding and modification of the serpin A1AT (α-1 antitrypsin). Consequently, addition of A1AT to plasma increased bacterial survival. Sequestration of A1AT by SpeB led to enhanced contact system activation, supported by increased bacterial growth in prekallikrein deficient plasma. In a mouse model of systemic infection, administration of SpeB reduced significantly bacterial dissemination. The findings reveal an additional layer of complexity to host-microbe interactions that may be of benefit in the treatment of severe bacterial infections.
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen N, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Meinert Niclasen
authors.forename: Johan G
authors.initials: JG
authors.lastname: Olsen
authors.forename: Robert
authors.initials: R
authors.lastname: Dagil
authors.forename: Zhang
authors.initials: Z
authors.lastname: Qing
authors.forename: Ole E
authors.initials: OE
authors.lastname: Sørensen
authors.forename: Birthe B
authors.initials: BB
authors.lastname: Kragelund
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D013290:Streptococcal Infections / Q000378:metabolism / Q000382:microbiology; D013297:Streptococcus pyogenes; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D005098:Exotoxins; D000515:alpha 1-Antitrypsin; C027951:erythrogenic toxin