Abstract
Upon host infection, the human pathogenic microbe Staphylococcus aureus (S. aureus) immediately faces innate immune reactions such as the activated complement system. Here, a novel innate immune evasion strategy of S. aureus is described. The staphylococcal proteins surface immunoglobulin-binding protein (Sbi) and extracellular fibrinogen-binding protein (Efb) bind C3/C3b simultaneously with plasminogen. Bound plasminogen is converted by bacterial activator staphylokinase or by host-specific urokinase-type plasminogen activator to plasmin, which in turn leads to degradation of complement C3 and C3b. Efb and to a lesser extend Sbi enhance plasmin cleavage of C3/C3b, an effect which is explained by a conformational change in C3/C3b induced by Sbi and Efb. Furthermore, bound plasmin also degrades C3a, which exerts anaphylatoxic and antimicrobial activities. Thus, S. aureus Sbi and Efb comprise platforms to recruit plasmin(ogen) together with C3 and its activation product C3b for efficient degradation of these complement components in the local microbial environment and to protect S. aureus from host innate immune reactions.
Highlights
Staphylococcus aureus, a persisting human pathogen, can cause a variety of diseases including skin infections, pneumonia, endocarditis, and sepsis [1,2]
Immobilized surface immunoglobulin-binding protein (Sbi) or extracellular fibrinogen-binding protein (Efb) was incubated with biotin-labeled plasminogen (PLGb) and binding was assayed by Enzyme linked Immunosorbent Assay (ELISA)
Plasminogen binding to Sbi and Efb was similar to the previously identified plasminogen ligand CRASP-5 of Borrelia burgdorferi [30,31], (Fig. 1A+B)
Summary
Staphylococcus aureus, a persisting human pathogen, can cause a variety of diseases including skin infections, pneumonia, endocarditis, and sepsis [1,2]. S. aureus is immediately recognized and targeted by innate immune responses, such as the complement system. Activation of complement by foreign surfaces (alternative pathway, AP), by antibodies (classical pathway, CP) or by mannan (lectin pathway, LP) causes microbial opsonization, leukocyte recruitment, and cell lysis. All three pathways lead to the cleavage of C3 and subsequent formation of anaphylatoxin C3a and opsonin C3b. C3a attracts and activates granulocytes; whereas C3b attaches covalently to the bacterial surface, amplifies complement activation, and thereby labels cells for phagocytosis. C3b deposition leads to inflammatory reactions and formation of the pore-forming terminal complement complex [3,4,5]
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