Staphylococcal extracellular adherence protein induces platelet activation by stimulation of thiol isomerases

Bertling, A., Niemann, S., Hussain, M., Holbrook, L., Stanley, R. G., Brodde, M. F., Pohl, S., Schifferdecker, T., Roth, J., Jurk, K., Müller, A., Lahav, J., Peters, G., Heilmann, C., Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352 and Kehrel, B. E. (2012) Staphylococcal extracellular adherence protein induces platelet activation by stimulation of thiol isomerases. Arteriosclerosis Thrombosis and Vascular Biology, 32. pp. 1979-1990. ISSN 1079-5642 doi: 10.1161/ATVBAHA.112.246249

Abstract/Summary

OBJECTIVE: Staphylococcus aureus can induce platelet aggregation. The rapidity and degree of this correlates with the severity of disseminated intravascular coagulation, and depends on platelet peptidoglycans. Surface-located thiol isomerases play an important role in platelet activation. The staphylococcal extracellular adherence protein (Eap) functions as an adhesin for host plasma proteins. Therefore we tested the effect of Eap on platelets. METHODS AND RESULTS: We found a strong stimulation of the platelet-surface thiol isomerases protein disulfide isomerase, endoplasmic reticulum stress proteins 57 and 72 by Eap. Eap induced thiol isomerase-dependent glycoprotein IIb/IIIa activation, granule secretion, and platelet aggregation. Treatment of platelets with thiol blockers, bacitracin, and anti-protein disulfide isomerase antibody inhibited Eap-induced platelet activation. The effect of Eap on platelets and protein disulfide isomerase activity was completely blocked by glycosaminoglycans. Inhibition by the hydrophobic probe bis(1-anilinonaphthalene 8-sulfonate) suggested the involvement of hydrophobic sites in protein disulfide isomerase and platelet activation by Eap. CONCLUSIONS: In the present study, we found an additional and yet unknown mechanism of platelet activation by a bacterial adhesin, involving stimulation of thiol isomerases. The thiol isomerase stimulatory and prothrombotic features of a microbial secreted protein are probably not restricted to S aureus and Eap. Because many microorganisms are coated with amyloidogenic proteins, it is likely that the observed mechanism is a more general one.