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，并导致败血症的病死率异常高。肺炎链球菌是全球主要的细菌病原体，也是CAP和败血症的原因。ACE的风险在肺炎球菌感染后的十年内仍然升高。新的方法来管理和治疗的感染是迫切需要的，但这是阻碍了有限的机械理解疾病processes.This项目将探讨病原体和宿主在ACE的病理生理过程中肺炎球菌感染的作用。使用新的方法，我们已经开发了用于研究感染期间的微生物进化-实时-我们将确定脓毒症期间选择的肺炎球菌基因组的位点。CRISPR编辑将用于创建点突变和顺序基因缺失，以识别导致进化菌株表型的遗传因素。组织病理学和体内感染成像将被用来机械调查细菌的决定因素的毒力在blood.The项目的第二个方面将是了解脓毒症，免疫thromobosis和血管凝血肺炎球菌感染之间的联系。为了控制病原体的传播，中性粒细胞释放它们的DNA、抗菌肽和组蛋白以形成网状结构，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。对患有脓毒症的小鼠和人类的血液样本进行分析将描述导致不受控制的NETosis的因素。内部开发的用于定量心脏病理学和ACE的其他宿主贡献者的定制测定将用于疾病过程的进一步研究。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，炎症和免疫决定因素。该项目探讨了病原体-宿主界面，考虑到两者对感染性疾病过程的贡献。继发于细菌性肺炎和脓毒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，加上结构和计算研究，将为新的治疗方法提供信息，并有助于确定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确的医学方法。

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