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

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 vivo
imaging 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 aids
in 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