title: M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage.
abstract: Increased vascular permeability is a key feature of inflammatory conditions. In severe infections, leakage of plasma from the vasculature induces a life-threatening hypotension. Streptococcus pyogenes, a major human bacterial pathogen, causes a toxic shock syndrome (STSS) characterized by excessive plasma leakage and multi-organ failure. Here we find that M protein, released from the streptococcal surface, forms complexes with fibrinogen, which by binding to beta2 integrins of neutrophils, activate these cells. As a result, neutrophils release heparin binding protein, an inflammatory mediator inducing vascular leakage. In mice, injection of M protein or subcutaneous infection with S. pyogenes causes severe pulmonary damage characterized by leakage of plasma and blood cells. These lesions were prevented by treatment with a beta2 integrin antagonist. In addition, M protein/fibrinogen complexes were identified in tissue biopsies from a patient with necrotizing fasciitis and STSS, further underlining the pathogenic significance of such complexes in severe streptococcal infections.
authors.affiliation: Department of Cell and Molecular Biology, Lund University, Tornavägen 10, S-221 84 Lund, Sweden. heiko.herwald@medkem.lu.se
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
authors.forename: Henning
authors.initials: H
authors.lastname: Cramer
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Wayne
authors.initials: W
authors.lastname: Russell
authors.forename: Ulla
authors.initials: U
authors.lastname: Sollenberg
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
authors.forename: Hans
authors.initials: H
authors.lastname: Flodgaard
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindbom
authors.forename: Lars
authors.initials: L
authors.lastname: Björck
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D018821:CD18 Antigens / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism; D046911:Macromolecular Substances; D008670:Metals / Q000378:metabolism; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000382:microbiology / Q000503:physiopathology; D012772:Shock, Septic / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013290:Streptococcal Infections / Q000150:complications*; D013297:Streptococcus pyogenes / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D018821:CD18 Antigens; D002352:Carrier Proteins; D018836:Inflammation Mediators; D007477:Ions; D026563:LDL-Receptor Related Protein-Associated Protein; D046911:Macromolecular Substances; D008670:Metals; D010446:Peptide Fragments; C014689:streptococcal M protein; D005340:Fibrinogen