Population genomic identification of bacterial traits linked to the outcome of Legionnaires' disease

With the increasing abundance of low-cost draft and whole-genome sequence data, genomics is rapidly developing our understanding of the evolution, adaption and emergence of virulence in medically significant groups of bacteria. In this project, I will use an array of tools to conduct a genomic investigation of the genus Legionella
that contains several pathogens, most notably Legionella pneumophila. This ubiquitous intracellular pathogen of environmental protozoa is commonly found in freshwater reservoirs but can survive inside alveolar macrophages to cause disease in humans (legionellosis), responsible for the severe community-acquired pneumonia known as Legionnaires' disease (LD) and the similar but less severe Pontiac disease. The majority of infections are sporadic and travel-related (60%) but outbreaks can occur in the community or in hospitals following contamination of man-made water systems (e.g. industrial cooling towers), which are thought to be the main reservoirs for infection. Several major outbreaks in Scotland have resulted in considerable morbidity and mortality, with significant associated economic costs to NHS Scotland.

I will build on previous work in the lab, which has employed comparative genomic analysis to trace the origin of outbreaks in Scotland, revealing considerable genetic variation among clinical isolates and differences in gene content among clinical and environmental strains. In particular, for the major LD outbreak in Edinburgh in 2012, a correlation between virulence gene content and the outcome of severe respiratory infection was identified. 6 recently emerged clones have been identified to account for the majority of clinical cases of legionellosis worldwide but our understanding of the basis for the recent emergence of these clinically relevant clones is very limited. Additionally, recent evidence has suggested that Legionella may be adapting to man-made water systems and towards a human host-association leading to the global spread of clones, although this is not yet well understood.

In this project, I will use genomic data to try and dissect the basis for the recent emergence of pathogenic Legionella and the strain-dependent variation in the outcome of infection. A global phylogenetic analysis of over 900 sequences from Legionella pneumophila and closely-related spp will be performed, aiming to trace the recent emergence of the pathogenic clones and identify key genetic events in their clonal expansion. This will include over 900 sequences of clinical, man-made water environmental and natural water isolates that have been previously generated or are publicly available. GWAS will be used to try and identify traits associated with adaptation to man-made water systems and to find the virulence traits most closely associated with poor clinical outcome in human infection. These analyses will be complemented with other comparative genomic analyses using a range of tools, focusing on traits linked with enhanced virulence (and poor clinical outcome in human infection), antimicrobial resistance and host adaptation.