Abstract: The frequency and severity of bacteremic infections has increased over the last decade and bacterial endovascular infections (i.e., sepsis or endocarditis) are associated with high morbidity and mortality. Bacteria or secreted bacterial products modulate platelet function and, as a result, affect platelet accumulation at sites of vascular infection and inflammation. However, whether bacterial products regulate synthetic events in platelets is not known. In the present study, we determined if prolonged contact with staphylococcal α-toxin signals platelets to synthesize B-cell lymphoma (Bcl-3), a protein that regulates clot retraction in murine and human platelets. We show that α-toxin induced αIIbβ3-dependent aggregation (EC50 2.98 µg/mL ± 0.64 µg/mL) and, over time, significantly altered platelet morphology and stimulated de novo accumulation of Bcl-3 protein in platelets. Adherence to collagen or fibrinogen also increased the expression of Bcl-3 protein by platelets. α-toxin altered Bcl-3 protein expression patterns in platelets adherent to collagen, but not fibrinogen. Pretreatment of platelets with inhibitors of protein synthesis or the mammalian Target of Rapamycin (mTOR) decreased Bcl-3 protein expression in α-toxin stimulated platelets. In conclusion, Staphylococcus aureus-derived α-toxin, a pore forming exotoxin, exerts immediate (i.e., aggregation) and prolonged (i.e., protein synthesis) responses in platelets, which may contribute to increased thrombotic events associated with gram-positive sepsis or endocarditis.
Keywords: α-toxin; Bcl-3; protein synthesis
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Schubert, S.; Schwertz, H.; Weyrich, A.S.; Franks, Z.G.; Lindemann, S.; Otto, M.; Behr, H.; Loppnow, H.; Schlitt, A.; Russ, M.; Presek, P.; Werdan, K.; Buerke, M. Staphylococcus aureus α-Toxin Triggers the Synthesis of B-Cell Lymphoma 3 by Human Platelets. Toxins 2011, 3, 120-133.
Schubert S, Schwertz H, Weyrich AS, Franks ZG, Lindemann S, Otto M, Behr H, Loppnow H, Schlitt A, Russ M, Presek P, Werdan K, Buerke M. Staphylococcus aureus α-Toxin Triggers the Synthesis of B-Cell Lymphoma 3 by Human Platelets. Toxins. 2011; 3(2):120-133.
Schubert, Sebastian; Schwertz, Hansjörg; Weyrich, Andrew S.; Franks, Zechariah G.; Lindemann, Stephan; Otto, Monika; Behr, Hagen; Loppnow, Harald; Schlitt, Axel; Russ, Martin; Presek, Peter; Werdan, Karl; Buerke, Michael. 2011. "Staphylococcus aureus α-Toxin Triggers the Synthesis of B-Cell Lymphoma 3 by Human Platelets." Toxins 3, no. 2: 120-133.