Understanding adverse cardiac events in community-acquired pneumonia: how do bacterial and host factors contribute to severe infection outcomes

心脏并发症是超过四分之一的社区获得性肺炎（CAP）病例的特征。这些相关的心脏事件（ace）与死亡率增加有关，并导致败血症的极高病死率。肺炎链球菌是一种主要的全球性细菌病原体，也是CAP和败血症的病因。在肺炎球菌感染后的10年内，ace的风险仍然升高。目前迫切需要管理和治疗感染的新方法，但这受到对疾病过程的有限机制理解的阻碍。本项目将探讨病原体和宿主在肺炎球菌感染期间ace的病理生理中的作用。使用新的方法，我们已经开发了微生物进化的研究-实时-在感染期间，我们将确定在败血症期间选择的肺炎球菌基因组位点。crispr编辑将用于创建点突变和顺序基因缺失，以确定导致进化菌株最终表型的遗传因素。感染的组织病理学和体内成像将用于机械地研究血液中毒力的细菌决定因素。该项目的第二个方面将是了解败血症，免疫血栓形成和肺炎球菌感染血管凝固之间的联系。为了控制病原体的传播，中性粒细胞释放它们的DNA、抗菌肽和组蛋白形成网状结构，通过NETosis过程捕获病原体并帮助其清除。然而，不受控制的NETosis可能是致命的，因为它可以引起血管内凝血并最终导致多器官衰竭。对患有败血症的小鼠和人类的血液样本进行分析，将揭示导致NETosis失控的因素。内部开发的定制分析，用于量化心脏病理和ace的其他宿主贡献者，将用于进一步研究疾病过程。总的来说，这项工作将确定肺炎球菌肺炎和败血症期间心脏病理的微生物，炎症和免疫学决定因素。该项目探索病原体-宿主界面，考虑两者对传染病过程的贡献。继发于细菌性肺炎和败血症的心血管损伤与显著的发病率和死亡率相关。该项目的研究结果与结构和计算研究相辅相成，将为新的治疗方法提供信息，并有助于识别那些最有可能发生感染相关心脏并发症的人，从而实现个性化和精准医疗方法

Cardiac complications are a feature of more than a quarter of cases of community-acquired pneumonia (CAP). These associated cardiac events (ACEs) are linked to increased mortality and contribute to the exceptionally high case fatality rate of sepsis. Streptococcus pneumoniae is a major global bacterial pathogen and a cause of both CAP and sepsis. The risk of ACEs remains elevated for up to a decade post-pneumococcal infection. New approaches to the management and treatment of infection are urgently needed, but this is hampered by a limited mechanistic understanding of disease processes.This project will explore the roles of both pathogen and host in the pathophysiology of ACEs during pneumococcal infection. Using novel methods, we have developed for the study of microbial evolution - in real-time - during infection, we will identify sites of the pneumococcal genome that are under selection during sepsis. CRISPR-editing will be utilised to create point mutations and sequential gene deletions, to identify the genetic factors responsible for the resulting phenotype of the evolved strains. Histopathological and in vivoimaging of infection will be used to mechanistically investigate bacterial determinants of virulence in blood.The second aspect of the project will be to understand the link between sepsis, immunothromobosis and vascular coagulation in pneumococcal infections. In order to control the spread of pathogens, neutrophils release their DNA, antimicrobial peptides and histones to form a web-like structure, through a process of NETosis that entraps the pathogen and aidsin its clearance. Uncontrolled NETosis can be lethal, however, as it can cause intravascular coagulation and culminate in multi-organ failure. Analysis of blood samples from mice and humans with sepsis will delineate the factors responsible for uncontrolled NETosis. Bespoke assays, developed in-house, for quantification of other host contributors to cardiac pathology and ACEs will be used in further investigation of disease processes. Collectively, this work will define the microbial, inflammatory and immunological determinants of cardiac pathology during pneumococcal pneumonia and sepsis.The project explores the pathogen-host interface, considering the contribution both make to infectious disease processes. Cardiovascular damage, secondary to bacterial pneumonia and sepsis, is associated with significant morbidity and mortality. Findings from this project,complemented with structural and computational studies, will inform new therapeutic approaches and help to identify those who are most at risk of developing infection-associated cardiac complications, enabling personalised and precision medicine approaches