Molecular Events Underlying Group B Streptococcal Bloodstream Infection: The Role of the Platelet and Endothelium

Bloodstream infections carry a high economic and health burdenand can develop into invasive life-threatening conditions such as sepsis, meningitis and infective endocarditis, characterised byaberrant thrombus formation and endothelial dysregulation. The intestinal and vaginal microflora, Streptococcus agalactiae, commonly known as Group B Streptococcus (GBS), is the mostcommonneonatalinvasive bloodstream infection pathogenin the western world. The aim of this thesis was to investigate the molecularinteractions between GBS,platelets and endothelial cells and the potential value of these interactions inGBS bloodstream infectionmanagement.Here, we demonstrate a GBS strain dependent platelet and endothelialcell interaction. GBS signal driven platelet aggregation was dependent on the bacterial strain, trypsin sensitive bacterial surface proteins and immunoglobulin G.We have delineated the functional role of the platelet receptor FcγRIIain GBS driven thrombus formation using a microfluidic physiological shear flow system coupled with real time microscopy, revealingits non-involvement in the initial platelet rolling and adhesion interaction with GBSeven as GBS was shown to interact withplatelets optimally only at low shear rate (≤ 200 s-1). GBS strain dependent endothelial cell invasion was accompanied by endothelial cell damage and necrosis as seen in our flow cytometric analysis and electron micrograph of GBS infected endothelial cells. These endothelial abnormalities coincided with an increase in endothelial permeability as seenin our FITC-dextran monolayer flux analysis.While epidemiological studies suggest an association between GBS serotype and clonal complex groups with GBS pathogenicity,our observation of GBS strain dependent platelet and endothelial dysregulation reveals that predicting disease outcome, particularly thrombotic and endothelial dysfunction, based on serotype or clonal complex group could be misleading.Our studyhas revealedthe usefulness of the flow system in studying GBS platelet-bacterial interactions andadds to theevidence of FcγRIIaas a potential target in bacterial induced thrombosis.