Abstract
Impaired healing is common in wounds infected with the major human pathogen Staphylococcus aureus, although the underlying mechanisms are poorly understood. Here, we show that S. aureus lipoteichoic acid (LTA) inhibits platelet aggregation caused by physiological agonists and S. aureus and reduced platelet thrombus formation in vitro. The presence of D-alanine on LTA is necessary for the full inhibitory effect. Inhibition of aggregation was blocked using a monoclonal anti-platelet activating factor receptor (PafR) antibody and Ginkgolide B, a well-defined PafR antagonist, demonstrating that the LTA inhibitory signal occurs via PafR. Using a cyclic AMP (cAMP) assay and a Western blot for phosphorylated VASP, we determined that cAMP levels increase upon platelet incubation with LTA, an effect which inhibits platelet activation. This was blocked when platelets were preincubated with Ginkgolide B. Furthermore, LTA reduced hemostasis in a mouse tail-bleed assay.
Highlights
Staphylococcus aureus is an important opportunistic human pathogen and the cause of a large burden of morbidity and mortality
The ability of the pathogen to bind to and activate platelets, small (2–4 μm), blood cells responsible for maintaining normal hemostasis leads to the formation of platelet-bacteria thrombi on the surface of heart valves, which is required for the development of endocarditis since platelets attached to damaged valves serve as foci for attachment of bacteria circulating in the blood [1]
In this study we investigated lipoteichoic acid (LTA) inhibition of platelet aggregation
Summary
Staphylococcus aureus is an important opportunistic human pathogen and the cause of a large burden of morbidity and mortality. Several studies have shown that S. aureus binds platelets and induces their aggregation. Induction of thrombus formation by S. aureus has been characterized extensively, infection of wounds by this pathogen frequently results in impaired healing, the mechanisms of which are not fully understood [4]. S. aureus extracellular proteins Efb inhibits platelet aggregation by binding to fibrinogen [5]. Inhibition of platelet activity by Efb or pharmacological antagonists causes decreased killing of S. aureus in whole blood and increases the lethality of S. aureus infection in a mouse model [6]. S. aureus lipoteichoic acid (LTA) was previously shown to inhibit activation of platelets, a role in hemostasis its relevance to the S. aureus-platelet interaction and the mechanism(s) by which inhibition is achieved are not understood [7]. LTA inhibited activation of human platelets by physiological agonists and S. aureus. 2046 JID 2013:208 (15 December) Waller et al binding platelet activating factor receptor (PafR), a phospholipid receptor that binds LTA and is associated with an increased platelet intracellular cyclic adenosine monophosphate (cAMP) concentration
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