Deciphering the molecular mechanisms via which Streptococcus bacteria drive thrombosis and infective endocarditis

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"Heart disease is the leading cause of death in the developed world. Viridans group Streptococcus bacteria (VGS) are a major cause of infective endocarditis (IE), a severe form of heart disease characterised by clot formation on heart valves. IE has a high mortality rate, is lethal if untreated, and treatment often fails due to poor antibiotic penetration into infective clots or antibiotic resistance. This indicates an unmet clinical need for development of non-antibiotic-based strategies for the management of IE. This project aims to identify the precise molecular mechanisms by which VGS can survive within the bloodstream and drive the unwanted clot formation associated with IE. Such mechanistic understanding is a critical first step to the development of novel IE therapies.The association of VGS with IE derives from their capacity to bind and activate platelets on heart valves. Our work with VGS Streptococcus gordonii has shown that surface protein PadA is critical to IE pathogenesis. PadA triggers platelet activation via receptor GPIIbIIIa, modulates neutrophil extracellular trap (NET) formation, promotes bacterial survival in blood, and contributes to virulence in a rabbit IE model. However, how PadA mediates these effects at the molecular level is unknown. Furthermore, while studies have focused on S. gordonii, homologues of PadA are found across several VGS species but it is not known if these confer similar functional capabilities. This project will address these critical questions by first identifying the mechanisms via which PadA modulates platelet or neutrophil behaviour and promotes survival in blood. These studies will then be expanded to investigate the functional capabilities of PadA homologues in IE clinical isolates. To facilitate the design of potential targeted therapeutic strategies, detailed structural characterisation of PadA will be undertaken, including co-crystallisation studies with known ligands."