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: Heiko Herwald, Henning Cramer, Matthias Mörgelin, Wayne Russell, Ulla Sollenberg, Anna Norrby-Teglund, Hans Flodgaard, Lennart Lindbom, Lars Björck
• Journal: Cell (Cell) Vol. 116 Issue 3 Pg. 367-79 (Feb 06 2004) ISSN: 0092-8674 [Print] United States
• PMID: 15016372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antigens, Bacterial
• Bacterial Outer Membrane Proteins (metabolism, pharmacology)
• CD18 Antigens (drug effects, metabolism)
• Capillary Permeability (drug effects, physiology)
• Carrier Proteins (metabolism, 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, metabolism, ultrastructure)
• Peptide Fragments (pharmacology)
• Pneumonia (chemically induced, microbiology, physiopathology)
• Shock, Septic (etiology, metabolism, physiopathology)
• Signal Transduction (drug effects, physiology)
• Streptococcal Infections (complications)
• Streptococcus pyogenes (metabolism, pathogenicity)