Original Research: Focus on Platelets Mechanism of Outside-In IIb 3-Mediated Activation of Human Platelets by the Colonizing Bacterium, Streptococcus gordonii*

Objective—To better understand the mechanism of platelet recruitment and activation by Streptococcus gordonii. The oral bacterium Streptococcus gordonii, is amongst the most common pathogens isolated from Infective Endocarditis patients, and has the property of being able to activate platelets, leading to thrombotic complications. The mechanism of platelet recruitment and activation by S. gordonii is poorly understood. Methods and Results—Infective endocarditis is a bacterial infection of the heart valves that carries a high risk of morbidity and mortality. The oral bacterium, S gordonii, is among the most common pathogens isolated from patients with infective endocarditis and is able to activate platelets, leading to thrombotic complications. Platelets interact with S gordonii via glycoprotein Ib and IIb 3-recognizing S gordonii surface proteins haemaglutitin salivary antigen (Hsa) and platelet adherence protein A, respectively. The inhibition of glycoprotein Ib or IIb 3 using blocking antibodies or deletion of S gordonii Hsa or platelet adherence protein A significantly reduces platelet adhesion. Immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins have recently played a role in transmitting activating signals into platelets. Platelet adhesion to immobilized S gordonii resulted in tyrosine phosphorylation of the ITAM-bearing receptor, Fc RIIa, and phosphorylation of downstream effectors (ie, spleen tyrosine kinase [Syk] and phospholipase C [PLC]2). Tyrosine phosphorylation of Fc RIIa resulted in platelet-dense granule secretion, filopodial and lamellipodial extension, and platelet spreading. Inhibition of Fc RIIa ablated both dense granule release and platelet spreading. Conclusion—Streptococcus gordonii binding to the IIb 3/Fc RIIa integrin/ITAM signaling complex results in platelet activation that likely contributes to the thrombotic complications of infective endocarditis. (Arterioscler Thromb Vasc Biol. 2010;30:2408-2415.)