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主要原因。翠绿菌群链球菌（VGS）是感染性心内膜炎（IE）的主要原因，感染性心内膜炎是一种严重的心脏病，其特征是心脏瓣膜上形成血栓。IE死亡率高，如果不治疗是致命的，并且由于抗生素渗透到感染凝块或抗生素耐药性差，治疗往往失败。这表明，开发非抗生素为基础的IE管理策略的临床需求尚未得到满足。该项目旨在确定VGS在血液中存活的精确分子机制，并驱动与IE相关的不需要的凝块形成。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的关联源于它们结合和激活心脏瓣膜上血小板的能力。我们对VGS戈多氏链球菌的研究表明，表面蛋白PadA对IE的发病机制至关重要。在家兔IE模型中，PadA通过受体GPIIbIIIa触发血小板活化，调节中性粒细胞胞外陷阱（NET）的形成，促进血液中细菌的存活，并有助于增强毒力。然而，PadA如何在分子水平上介导这些作用尚不清楚。此外，虽然研究集中在S. gordonii上，但在几个VGS物种中发现了PadA的同源物，但不知道这些同源物是否具有相似的功能能力。该项目将通过首先确定PadA调节血小板或中性粒细胞行为并促进血液存活的机制来解决这些关键问题。这些研究将被扩展到在IE临床分离株中研究PadA同源物的功能能力。为了促进潜在靶向治疗策略的设计，将进行PadA的详细结构表征，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."