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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Bacterial*
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Bacterial Outer Membrane Proteins / metabolism*
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Bacterial Outer Membrane Proteins / pharmacology
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CD18 Antigens / drug effects
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CD18 Antigens / metabolism
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Capillary Permeability / drug effects
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Capillary Permeability / physiology*
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Carrier Proteins / metabolism*
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Carrier Proteins / pharmacology
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Chemotaxis, Leukocyte / physiology
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Disease Models, Animal
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Female
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Fibrinogen / metabolism*
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Humans
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In Vitro Techniques
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Inflammation Mediators / metabolism
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Ions / metabolism
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LDL-Receptor Related Protein-Associated Protein / metabolism
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Macromolecular Substances
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Metals / metabolism
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Mice
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Microscopy, Electron, Scanning
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Neutrophils / enzymology
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Neutrophils / metabolism
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Neutrophils / ultrastructure
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Peptide Fragments / pharmacology
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Pneumonia / chemically induced
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Pneumonia / microbiology
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Pneumonia / physiopathology
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Shock, Septic / etiology*
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Shock, Septic / metabolism
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Shock, Septic / physiopathology*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Streptococcal Infections / complications*
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Streptococcus pyogenes / metabolism
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Streptococcus pyogenes / pathogenicity
Substances
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Antigens, Bacterial
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Bacterial Outer Membrane Proteins
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CD18 Antigens
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Carrier Proteins
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Inflammation Mediators
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Ions
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LDL-Receptor Related Protein-Associated Protein
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Macromolecular Substances
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Metals
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Peptide Fragments
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streptococcal M protein
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Fibrinogen