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

在发达国家，心脏病是导致死亡的首要原因。绿弧菌群链球菌(VGS)是感染性心内膜炎(IE)的主要原因，IE是一种严重的心脏病，其特征是心脏瓣膜上形成凝块。IE的死亡率很高，如果不进行治疗是致命的，而且由于抗生素对感染性血栓的渗透性差或抗生素耐药性，治疗经常失败。这表明开发非抗生素治疗IE的策略的临床需求尚未得到满足。该项目旨在确定VGS在血流中存活并驱动与IE相关的有害血栓形成的确切分子机制。这种机制的理解是开发新的IE疗法的关键的第一步。VGS与IE的联系源于它们结合和激活心脏瓣膜上的血小板的能力。我们对VGS戈登链球菌的研究表明，表面蛋白PADA在IE发病机制中起关键作用。在兔IE模型中，PADA通过GPIIbIIIa受体激活血小板，调节中性粒细胞细胞外陷阱(NET)的形成，促进细菌在血液中的存活，并促进毒力。然而，PADA如何在分子水平上调节这些效应尚不清楚。此外，虽然研究主要集中在S.gordonii上，但在几个VGS物种中发现了PADA的同源物，但尚不清楚这些同源物是否具有类似的功能。该项目将首先确定PADA调节血小板或中性粒细胞行为并提高血液中存活率的机制，从而解决这些关键问题。然后，这些研究将扩大到调查PADA同源物在IE临床分离株中的功能能力。为了便于设计潜在的靶向治疗策略，将对PADA的结构进行详细的表征，包括与已知配体的共结晶研究。“

"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."