Abstract
Group A streptococcus (GAS) strains secrete the protein streptokinase (SK), which functions by activating host human plasminogen (hPg) to plasmin (hPm), thus providing a proteolytic framework for invasive GAS strains. The types of SK secreted by GAS have been grouped into two clusters (SK1 and SK2) and one subcluster (SK2a and SK2b). SKs from cluster 1 (SK1) and cluster 2b (SK2b) display significant evolutionary and functional differences, and attempts to relate these properties to GAS skin or pharynx tropism and invasiveness are of great interest. In this study, using four purified SKs from each cluster, new relationships between plasminogen-binding group A streptococcal M (PAM) protein and SK2b have been revealed. All SK1 proteins efficiently activated hPg, whereas all subclass SK2b proteins only weakly activated hPg in the absence of PAM. Surface plasmon resonance studies revealed that the lower affinity of SK2b to hPg served as the basis for the attenuated activation of hPg by SK2b. Binding of hPg to either human fibrinogen (hFg) or PAM greatly enhanced activation of hPg by SK2b but minimally influenced the already effective activation of hPg by SK1. Activation of hPg in the presence of GAS cells containing PAM demonstrated that PAM is the only factor on the surface of SK2b-expressing cells that enabled the direct activation of hPg by SK2b. As the binding of hPg to PAM is necessary for hPg activation by SK2b, this dependence explains the coinherant relationship between PAM and SK2b and the ability of these particular strains to generate the proteolytic activity that disrupts the innate barriers that limit invasiveness.
Highlights
Group A streptococcus (GAS) virulence is dependent on a functional human fibrinolytic system
As the binding of human plasminogen (hPg) to plasminogen-binding group A streptococcal M (PAM) is necessary for hPg activation by SK2b, this dependence explains the coinherant relationship between PAM and SK2b and the ability of these particular strains to generate the proteolytic activity that disrupts the innate barriers that limit invasiveness
In assays investigating the effects of protein factors and cells on rhPg activation by rSKs, the indicated amount of rPAMAP53, human fibrinogen (hFg) (Enzyme Research Laboratories, South Bend, IN), rM1SF370, or GAS cells was premixed with substrate S2251 and rGlu1-hPg in 10 mM Hepes/150 mM NaCl, pH 7.4, and the reaction was accelerated by the addition of rSK
Summary
GAS virulence is dependent on a functional human fibrinolytic system. Results: Functional differences between different strains of GAS streptokinases have been found. Group A streptococcus (GAS) strains secrete the protein streptokinase (SK), which functions by activating host human plasminogen (hPg) to plasmin (hPm), providing a proteolytic framework for invasive GAS strains. This strongly suggests that there is a coinherant relationship between sk2b and pam-expressing GAS strains and that the combination of sk2b and pam might play a key role in skin tissue tropism and strain invasiveness [16] These findings propose a strong coselective pressure behind the alleles, the functional effects resulting from this selective pressure remain unknown. Considering the strong coinheritance between PAM and SK2b, we attempted to identify the functional relationships between PAM and SK2b with regard to hPg activation using purified proteins cloned and expressed from primary GAS isolates of throat and skin infections. The results of these studies have identified the functional relationships between PAM and SK2b on hPg activation
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