This Article Full Text Full Text (PDF) All Versions of this Article: 28/2/335    most recent ATVBAHA.107.152058v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kerrigan, S. W. Articles by Cox, D. Search for Related Content PubMed PubMed Citation Articles by Kerrigan, S. W. Articles by Cox, D. Pubmed/NCBI databases Substance via MeSH

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:335.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Molecular Basis for Staphylococcus aureus–Mediated Platelet Aggregate Formation Under Arterial Shear In Vitro

Steven W. Kerrigan; Niamh Clarke; Anthony Loughman; Gerardene Meade; Timothy J. Foster; Dermot Cox

From Molecular and Cellular Therapeutics (S.W.K., N.C., G.M., D.C.), Royal College of Surgeons in Ireland, Dublin; and the Microbiology Department (A.L., T.J.F.), Moyne Institute of Preventive Medicine, Trinity College, Dublin, Ireland.

Correspondence to Dr Dermot Cox, Cardiovascular Infection Group, Molecular and Cellular Therapeutics, 123 St. Stephens Green, Dublin 2, Ireland. E-mail dcox{at}rcsi.ie

Abstract

Objective— Staphylococcus aureus is the most frequent causative organism of infective endocarditis (IE) and is characterized by thrombus formation on a cardiac valve that can embolize to a distant site. Previously, we showed that S aureus clumping factor A (ClfA) and fibronectin-binding protein A (FnBPA) can stimulate rapid platelet aggregation.

Methods and Results— In this study we investigate their relative roles in mediating aggregate formation under physiological shear conditions. Platelets failed to interact with immobilized wild-type S aureus (Newman) at shear rates <500 s^–1 but rapidly formed an aggregate at shear rates >800 s^–1. Inactivation of the ClfA gene eliminated aggregate formation at any shear rate. Using surrogate hosts that do not interact with platelets bacteria overexpressing ClfA supported rapid aggregate formation under high shear with a similar profile to Newman whereas bacteria overexpressing FnBPA did not. Fibrinogen binding to ClfA was found to be essential for aggregate formation although fibrinogen-coated surfaces only allowed single-platelets to adhere under all shear conditions. Blockade of the platelet immunoglobulin receptor FcRIIa inhibited aggregate formation.

Conclusions— Thus, fibrinogen and IgG binding to ClfA is essential for aggregate formation under arterial shear conditions and may explain why S aureus is the major cause of IE.

Both Staphylococcus aureus clumping factor A (Clf A) and fibronectin-binding protein A (Fnbp A) mediate rapid platelet aggregation. However, only Clf A can induce rapid aggregate formation under arterial shear conditions that is dependent on antibody and fibrinogen binding. The corresponding platelet receptors are GPIIb/IIIa and FcRIIa.

Key Words: Staphylococcus aureus • clumping factor A • aggregate formation • fibrinogen • IgG

This article has been cited by other articles:

				H. Muller, M. Renner, B. M. Helmke, C. End, C. Weiss, J. Poeschl, and J. Mollenhauer Deleted in Malignant Brain Tumors 1 is up-regulated in bacterial endocarditis and binds to components of vegetations J. Thorac. Cardiovasc. Surg., September 1, 2009; 138(3): 725 - 732. [Abstract] [Full Text] [PDF]