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.

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

“…1), as this fragment is more unstable than intact M1 protein, and thus provides a more stringent test of the mutations (9). An M1 protein fragment corresponding to the AB fragment is generated during conditions mimicking infection (15,16). In addition, the AB fragment is sufficient to bind Fg (9,17).…”

“…In particular, we focused on the B repeats of M1 (Fig. 1), which confer binding to human fibrinogen (Fg) in an interaction that is key to phagocytic resistance and proinflammatory activation seen during septic shock (14,15). The B repeats are composed of two 28-residue regions that differ slightly in sequence but are absolutely conserved in Fg-interacting residues.…”

Neutrophil-derived azurocidin alarms the immune system

“…These activate PMN to degranulate in the circulation [69], releasing proteins from all granule subsets, including azurocidin [68]. Degranulation of PMN was found to be causative of the subsequent lung damage and edema formation [69]. Interestingly, injection of antibodies to azurocidin abrogated the lung injury (unpublished observation), pointing at the central position of this protein in the pathogenesis of M1 protein-induced lung damage.…”

“…In the course of the infection, S. pyogenes shed M1 protein, which forms complexes with fibrinogen [68]. These activate PMN to degranulate in the circulation [69], releasing proteins from all granule subsets, including azurocidin [68]. Degranulation of PMN was found to be causative of the subsequent lung damage and edema formation [69].…”

Purified Igg F C-Binding Proteins From M22 Group a Streptococcus Are Able to Induce Experimental Glomerulonephritis

“…Эффект повышения концен-трации IgG наблюдается и у пациентов с острыми стрептококковыми инфекциями. Помимо IgG, белки М семейства могут связывать и другие белки плазмы крови: фибронектин, фибриноген, плаз-миноген, альбумин, IgA и компоненты компле-мента [16,19,21]. Взаимодействие стрептококков с таким широким кругом белков крови не может пройти для организма-хозяина бесследно.…”