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Title: Host-pathogen interactions influencing susceptibility to infective endocarditis
Author: Daga, Shruti
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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Introduction: Bacterial-platelet-fibrin complexes (vegetations), form on cardiac valves in infective endocarditis and are associated with increased morbidity and mortality. Although the mechanisms of bacterium-platelet adhesion, platelet activation and aggregation that are likely to contribute to vegetation formation have been identified, experimental conditions employed in these studies do not accurately reflect bacterial growth in the human vasculature. In addition, the contribution of host genetic factors such as platelet receptor polymorphisms to the pathogenesis of infective endocarditis is unknown. Considering that Staphylococcus aureus is now the most common cause of infective endocarditis associated with a poor prognosis, the contribution of bacterial and host factors to bacterium-platelet interactions, platelet activation and severity of infective endocarditis were analysed. Methods and results: Influence of bacterial growth environment on S. aureus-platelet interactions: Platelet aggregometry was performed with a range of S. aureus clinical and genetically modified isolates grown in nutrient broth and whole human blood. Some strains grown in nutrient broth failed to induce platelet aggregation, whereas all S. aureus isolates induced platelet aggregation after growth in blood. S. aureus surface proteins clumping factors A and B, serine-aspartate repeats C, D and E, iron-regulated surface determinants A and B and staphylococcal protein A were not essential for platelet aggregation induced by S. aureus grown in human blood, but the lag time to aggregation was increased in a strain containing mutations in genes encoding fibronectin-binding proteins A and B. Correlation between platelet activation and susceptibility to infective endocarditis: Platelet activation was determined in patients with infective endocarditis using flow cytometry. Platelet P-selectin expression was reduced in patients with infective endocarditis as compared to healthy volunteers, but was higher in patients requiring surgery. Influence of host genetic polymorphisms on S. aureus-platelet interactions and outcome in infective endocarditis: Flow cytometry and platelet aggregometry were performed to determine the role of specific platelet receptor GPIIIa piAI/A2, GPIb Kozak sequence, human platelet antigen (HPA)-2, variable number of tandem repeats (VNTR) and FcγRIIa H131R polymorphisms in S. aureus-platelet interactions. The GPIIIa P1A1/A1 genotype, FcγRIIa H allele and GPIb Kozak sequence polymorphism were associated with increased S. aureus-induced platelet aggregation. GPIb VNTR alleles influenced aggregate formation in vitro and development of vegetations in patients with infective endocarditis. The GPIb HPA-2a/2a genotype was associated with increased incidence of the composite clinical end-point of embolism, heart failure, need for surgery and mortality in patients with infective endocarditis. Conclusions: These studies have indicated that host and bacterial factors influence infective endocarditis and S. aureus-platelet interactions under conditions reflective of the host environment. Bacterial factors expressed during growth in human blood, host platelet activation levels and platelet receptor polymorphisms may represent novel prognostic markers and therapeutic targets in infective endocarditis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available