| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Research Abstract |
Staphylococcus aureus is a major pathogen of Gram-positive septic shock, frequently associated with consumption of plasma kininogen. We examined the vascular leakage (VL) activity of two cysteine proteinases secreted by Staphylococcus aureus. Proteolytically active staphopain A (ScpA) induced VL in a bradykinin B_2-receptor-dependent manner in guinea pig skin. This effect was augmented by staphopain B (SspB), which, by itself, had no VL activity. ScpA also produced VL activity from human plasma, apparently by acting directly on kininogens to release bradykinin, which was again significantly augmented by SspB. Intravenous injection of ScpA into a guinea pig caused bradykinin B_2-receptor-dependent hypotension. Interestingly, ScpA and SspB together induced the release of leucyl-methionyl-lysyl-bradykinin, a novel kinin with VL and blood pressure-lowering activities equivalent to bradykinin. Collectively, these data suggest that production of bradykinin and leucyl-methionyl-lysyl-bradykinin by staphopains is a new mechanism of Staphylococcus aureus virulence and bacterial shock. ScpA shortened human plasma partial activated thromboplastin time and prothrombin time but SspB prolonged them. No effect of ScpA on factor IX-deficient plasma suggested that factor IX activation is the major mechanism of ScpA coagulation induction effect. SspB prolonged thrombin time of both plasma and fibrinogen, indicating fibrinogenolytic activity of SspB. Staphopans did not cause platelet aggregation. These data may show implications of staphopains with disseminated intravascular coagulation (DIC) and subsequent bleeding tendency. Therefore, staphopain-specific inhibitors and kinin-receptor antagonists could be used to treat septic shock and DIC caused by Staphylococcus aureus.
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