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