• Heiko Herwald, Henning Cramer, Matthias Mörgelin, Wayne Russell, Ulla Sollenberg, Anna Norrby-Teglund, Hans Flodgaard, Lennart Lindbom, and Lars Björck.
• Department of Cell and Molecular Biology, Lund University, Tornavägen 10, S-221 84 Lund, Sweden. heiko.herwald@medkem.lu.se
• Cell. 2004 Feb 6; 116 (3): 367-79.

AbstractIncreased 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.

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