Abstract
Staphylococcus aureus is a major pathogen of gram-positive septic shock and frequently is associated with consumption of plasma kininogen. We examined the vascular leakage (VL) activity of two cysteine proteinases that are secreted by S. aureus. Proteolytically active staphopain A (ScpA) induced VL in a bradykinin (BK) B2-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 BK, which again was augmented significantly by SspB. Intravenous injection of ScpA into a guinea pig caused BK B2-receptor–dependent hypotension. ScpA and SspB together induced the release of leucyl-methionyl-lysyl-BK, a novel kinin with VL and blood pressure–lowering activities that are equivalent to BK. Collectively, these data suggest that production of BK and leucyl-methionyl-lysyl-BK by staphopains is a new mechanism of S. aureus virulence and bacterial shock. Therefore, staphopain-specific inhibitors and kinin-receptor antagonists could be used to treat this disease.
Highlights
Because staphopain A (ScpA) showed no vascular leakage (VL) activity when inactivated by E-64, a cysteine proteinase inhibitor, the proteolytic activity of the enzyme is linked to production of VL activity (Figs. 1 and 2)
HOE140, a BK B2 receptor antagonist, strongly inhibited VL that was induced by ScpA, a mixture of ScpA and SspB, or BK, but not the reaction that was caused by histamine (Fig. 2, inset)
The fast generation of VL activity from human plasma by ScpA decreases the chance of enzyme clearance from the circulation and suggests that these proteinases may cause septic shock in cases of severe human S. aureus infection
Summary
S. aureus induces the release of bradykinin (BK; reference 10), the final product of plasma kallikrein/kinin system activation which causes vascular leakage (VL; reference 11) and leads to hypotension This bacterium has a high negative net surface charge because of the presence of cell wall teichoic acid and lipoteichoic acid [12], and can activate the plasma kallikrein/kinin system as efficiently as LPS and lipid A from gram-negative bacteria in vitro [13]. These cell wall molecules may activate the plasma kallikrein/kinin system in S. aureus bacteremia.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
