Group A streptococci are significant human pathogens associated with a variety of diseases including pharyngitis, impetigo, and invasive infections such as cellulitis and bacteremia. Recently, the incidence and severity of streptococcal disease has increased, and the exact nature of the invasive phenotype has not been fully elucidated. We have isolated and characterized a streptococcal surface receptor with unique binding potential for the key fibrinolytic enzyme, plasmin. Plasmin, bound to a surface receptor on group A streptococci, maintains enzymatic activity, hydrolyzes its normal physiological substrate fibrin, and eludes regulation by its specific protease inhibitor, alpha2-antiplasmin. Group A streptococci are also known to secrete streptokinase, which activates human plasminogen to the enzyme, plasmin. We have demonstrated that group A streptococci, grown in human plasma, can secrete a plasminogen activator and capture the resulting active plasmin to cell surface receptors in the presence of normal plasma regulators. Plasmin, in addition to its role in fibrinolysis, also affects a variety of other biological processes including tissue remodeling, trophoblast implantation, and metastatic spread of tumors. These activities are associated with the broad substrate specificity of plasmin and its ability to degrade fibronectin and basement membranes. Bacterial-associated plasmin, in a unregulated form, would be able to activate latent collagenases and degrade tissue barriers, which may contribute to the invasive potential of streptococci. The focus of the proposed studies is to analyze the role of the plasmin receptor and the host plasminogen system in the pathogenesis of streptococcal infections. In order to establish the importance of this coupled system in the invasive properties of group A streptococci, the following specific aims will be addressed: 1. Identify functional domains of the plasmin receptor protein using biochemical and genetic approaches. 2. Generate isogenic strains of group A streptococci with mutations of the plasmin receptor gene. 3. Determine the contribution of the plasminogen system to bacterial invasiveness using an animal model. 4. Characterize plasminogen activator production and plasmin receptor expression for invasive streptococcal isolates.
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