An integrated metagenomic approach to understanding disease heterogeneity in severe sepsis due to community acquired pneumonia

Sepsis is a severe, life-threatening condition that may develop following an infection. An immune response is triggered, causing organs such as the lungs, heart and kidneys to fail. Many patients with sepsis are admitted to intensive care and it remains a major cause of death and long-term disability worldwide. In the UK, severe sepsis has a mortality rate of 35%.

Evidence suggests that a person's genes play a large role in determining their susceptibility to developing sepsis and their subsequent outcome from this condition. A major obstacle to interpreting this genetic association is that sepsis is a diverse condition with a variety of causative organisms and infection types. Community acquired pneumonia (CAP) is the commonest cause of severe sepsis. Current laboratory techniques are limited in identifying the culprit organism, which remains unknown in approximately one-third of patients with sepsis due to CAP.

The aim of my research is to better establish the causative organism in patients with sepsis from CAP and to use this knowledge to help us understand and interpret human genetic data. In this project, we will use a powerful new technique known as metagenomic profiling to sequence the genes of viruses and bacteria directly from patient blood samples. This will potentially allow us to identify the organism responsible for disease in a higher proportion of patients. Specifically, we hope to define the role of viral and bacterial coinfection which evidence suggests is underestimated in this patient group.

An improved understanding of the underlying cause of sepsis has the potential to transform a wide range of experimental studies and clinical trials of this condition. This proposal will utilise the information from metagenomic profiling to improve our understanding of the patterns of human genes that are switched on following infection. The hope is that by better understanding the role an individual's genes play, we can develop new therapies which are specifically tailored to individual patients. This will be particularly valuable as pathogens become more resistant to current antibiotics and anti-viral drugs.

As an Intensive Care Medicine specialist trainee who has seen the devastating effects of sepsis firsthand and faced the inadequacy of currently available treatment options, I have both a scientific and clinical interest in this condition and strongly believe this research has the potential to impact patient care. The work will be conducted at the internationally renowned Wellcome Trust Centre for Human Genetics at the University of Oxford, supervised by two senior academic physicians.

Sepsis represents a major public health burden worldwide with significant associated morbidity and mortality. Evidence suggests that susceptibility to sepsis and clinical outcome is modulated by genetic factors. However, current research has been limited by a complex, heterogeneous disease phenotype.

Community acquired pneumonia (CAP) is the commonest cause of sepsis. Its diverse microbial aetiology remains elusive in one-third of intensive care patients and evidence suggests we underestimate the role of viral and bacterial coinfection. This fellowship aims to advance our understanding of the aetiology and host response in severe sepsis due to CAP by building on an established cohort of patients recruited through the UK Genomic Advances in Sepsis (GAinS) study.

I will utilise next-generation sequencing techniques to analyse the nucleic acids of viral and bacterial species in patient plasma samples, enabling more accurate classification of disease aetiology. This metagenomic profiling will be used to inform and extend the genomic and transcriptomic analyses performed to date for the GAinS cohort, including analysis of gene expression signatures and integration with expression quantitative trait loci mapping and a genome-wide association study of sepsis survival. This integrated approach has the potential to enable clearer resolution of biological processes and define novel therapeutic targets in sepsis.

Commercial impact: Data from this project will be of potential value to private sector firms seeking to develop (a) diagnostic techniques relating to the identification of pathogens causing infectious disease, and (b) novel therapies for sepsis and pneumonia. Regarding the latter, although it is not anticipated that novel therapies will be developed during the lifetime of the project, an improved understanding of sepsis pathophysiology may identify therapeutic targets for future development. Thus, this project will support innovation and enterprise.

Policy-makers: Potential areas of public health benefit arising from this project include (a) an improved understanding of the organisms causing sepsis due to community-acquired pneumonia, and (b) the use of next-generation sequencing as a tool in clinical microbiology laboratories. Data from this project may inform evidence-based policy-making and influence the allocation of resources within the NHS. This includes the planning and provision of drugs and services relating to the specialties of critical care, infectious diseases and microbiology. There is relevance to planning for future influenza pandemics.

Research councils: This project will provide data to inform decision-making regarding clinically and scientifically important areas or research that should be funded in the future. Specifically, this will relate to research regarding the development of metagenomic techniques as well as the genetics of infection and immunity.

Patient groups: National and international sepsis patient support groups will be able to use an improved understanding of sepsis pathophysiology to counsel patients and relatives as well as lobby policy makers, research funders and the pharmaceutical industry.

Training of staff: Researchers involved in this project will develop specific technical skills and generic research skills that will be applicable to other environments. Potential areas that may benefit from the training of highly skilled researchers include the public sector (clinical practice within the NHS, academic institutions) as well as the private sector (pharmaceutical and biotechnology companies). Specifically, by receiving training to progress my career as an academic clinician in Anaesthesia and Intensive Care Medicine, I will be well placed to lead and support current and future research relating to critically ill patients and to promote evidence-based clinical practice. This will be particularly valuable since Anaesthesia and Intensive Care Medicine are significantly under-represented specialties in Academic Medicine.