Abstract
Dimeric M-proteins (M-Prt) in group A Streptococcus pyogenes (GAS) are surface-expressed virulence factors implicated in processes that contribute to the pathogenicity of infection. Sequence analyses of various GAS M-Prts have shown that they contain a highly conserved sortase A-dependent cell wall-anchored C terminus, whereas the surface-exposed N terminus is highly variable, a feature used for identification and serotyping of various GAS strains. This variability also allows for strain-specific responses that suppress host defenses. Previous studies have indeed identified the N-terminal M-Prt B-domain as the site interacting with antiphagocytotic human-host fibrinogen (hFg). Herein, we show that hFg strongly interacts with M-Prts containing highly variable B-domains. We further demonstrate that specific GAS clinical isolates display high affinity for the D-domain of hFg, and this interaction allowed for subsequent surface binding of human-host plasminogen (hPg) to the E-domain of hFg. This GAS surface-bound hPg is then activated by GAS-secreted streptokinase, leading to the generation of an invasive proteolytic bacterial surface. Our results underscore the importance of the human fibrinolytic system in host-pathogen interactions in invasive GAS infections.
Highlights
The Gram-positive bacterium, Streptococcus pyogenes, or group A Streptococcus (GAS)2 is responsible for wide-ranging pathological outcomes in its human hosts
PAM-containing strains are more common in invasive skin infections, strains implicated in recent streptococcal outbreaks in the United States and Europe express other M-Prt types [19, 22]
We document that M-Prts associated with these strains are dependent upon host fibrinogen (hFg) to recruit host plasminogen (hPg) to their surface and utilize SK2a for hPg activation
Summary
Dimeric M-proteins (M-Prt) in group A Streptococcus pyogenes (GAS) are surface-expressed virulence factors implicated in processes that contribute to the pathogenicity of infection. Sequence analyses of various GAS M-Prts have shown that they contain a highly conserved sortase A-dependent cell wall-anchored C terminus, whereas the surface-exposed N terminus is highly variable, a feature used for identification and serotyping of various GAS strains. This variability allows for strainspecific responses that suppress host defenses. M-Prts and ML-Prts can function as epithelial and endothelial cell adherence mediators, as suppressors of the innate immune response in tissues, and as receptors for surface protease recruitment, all of which enhance GAS strain-specific interactions with host components and, bacterial virulence. Based on sequence analyses of the -region of SK, GAS strains may be classified into two main groups, cluster 1 and cluster 2, the
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