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

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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