title: Protein C inhibitor--a novel antimicrobial agent.
abstract: Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity.
authors.affiliation: Department of Clinical Sciences, Section for Clinical and Experimental Infection Medicine, Lund University, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Malmström
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.forename: Linda
authors.initials: L
authors.lastname: Johansson
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
authors.forename: Oonagh
authors.initials: O
authors.lastname: Shannon
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
mesh_terms: D000890:Anti-Infective Agents; D001665:Binding Sites; D001792:Blood Platelets / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008081:Liposomes / Q000378:metabolism*; D015539:Platelet Activation; D018046:Protein C Inhibitor / Q000276:immunology* / Q000494:pharmacology; D013297:Streptococcus pyogenes / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D008081:Liposomes; D018046:Protein C Inhibitor