Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection

Abstract

Background. Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear. Methods. Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms - (1) linked to its own promoter and (2) fused to the promoter of the protein A gene - which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production. Results. Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain. Conclusions. The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis.