Use of a Human-Like Low-Grade Bacteremia Model of Experimental Endocarditis To Study the Role of Staphylococcus aureus Adhesins and Platelet Aggregation in Early Endocarditis

Abstract

ABSTRACTAnimal models of infective endocarditis (IE) induced by high-grade bacteremia revealed the pathogenic roles ofStaphylococcus aureussurface adhesins and platelet aggregation in the infection process. In humans, however,S. aureusIE possibly occurs through repeated bouts of low-grade bacteremia from a colonized site or intravenous device. Here we used a rat model of IE induced by continuous low-grade bacteremia to explore further the contributions ofS. aureusvirulence factors to the initiation of IE. Rats with aortic vegetations were inoculated by continuous intravenous infusion (0.0017 ml/min over 10 h) with 106CFU ofLactococcus lactispIL253 or a recombinantL. lactisstrain expressing an individualS. aureussurface protein (ClfA, FnbpA, BCD, or SdrE) conferring a particular adhesive or platelet aggregation property. Vegetation infection was assessed 24 h later. Plasma was collected at 0, 2, and 6 h postinoculation to quantify the expression of tumor necrosis factor (TNF), interleukin 1α (IL-1α), IL-1β, IL-6, and IL-10. The percentage of vegetation infection relative to that with strain pIL253 (11%) increased when binding to fibrinogen was conferred onL. lactis(ClfA strain) (52%;P= 0.007) and increased further with adhesion to fibronectin (FnbpA strain) (75%;P< 0.001). Expression of fibronectin binding alone was not sufficient to induce IE (BCD strain) (10% of infection). Platelet aggregation increased the risk of vegetation infection (SdrE strain) (30%). Conferring adhesion to fibrinogen and fibronectin favored IL-1β and IL-6 production. Our results, with a model of IE induced by low-grade bacteremia, resembling human disease, extend the essential role of fibrinogen binding in the initiation ofS. aureusIE. Triggering of platelet aggregation or an inflammatory response may contribute to or promote the development of IE.