DiMeN Doctoral Training Partnership: Use of genomics to characterise Pseudomonas aeruginosa horizontal gene transfer in non-CF bronchiectasis lung infections

"The adaptation and evolution of pathogens is facilitated by horizontal gene transfer events mediated via transmissible elements such as phages and plasmids. Usually, we only see these events retrospectively by using whole genome sequencing of isolates to identify plasmids, integrated genomic islands or prophages, from which we infer past gene transfer events. However, the role of phages in driving adaptation processes during infections is not well understood. We will use chronic lung infections with Pseudomonas aeruginosa as a model system to study these processes.

It is clear that the genomes of clinical isolates of Pseudomonas aeruginosa carry multiple prophages, and we have shown that such phages can be highly active during chronic lung infections (http://www.nature.com/ismej/journal/v9/n6/abs/ismej2014223a.html). In addition, it is known that free phage production can be triggered by antibiotic therapy. Using experimental evolution we have shown that phages can drive the evolution of P. aeruginosa populations (http://www.pnas.org/content/113/29/8266.abstract). In a separate project, as part of the MRC-funded Bronch-UK network (https://www.bronch.ac.uk/), we have found that multiple clones (lineages) of P. aeruginosa often co-exist in patients. This co-existence of closely related pathogens comprises an ideal system for gene transfer events such as those mediated by phages.

As part of the MRC-funded project, we have assembled a large database of P. aeruginosa genomes from multiple patients attending centres across the UK, and have identified examples of patients co-infected by more than one lineage of P. aeruginosa. Under the remit of the Bronch-UK network, bringing together nine clinical centres to assemble patient cohorts (n=1500), we are collecting further isolates, and will be able to identify many more examples of co-infection.

In this project, we will (a) screen a larger number of bronchiectasis samples for evidence of co-infection with more than one lineage of P. aeruginosa, (b) use bioinformatics approaches to analyse the genomes of isolates from the sputa of bronchiectasis patients to identify and characterise co-infecting lineages that share elements of their accessory genome (including prophages), and (c) using evolutionary biology, to model suspected transfer events (and the role of antibiotics) in an artificial sputum biofilm model system designed to recapitulate the sputum environment.

This PhD project will be supervised by the interdisciplinary team of Professor Craig Winstanley (Infection & Global Health, University of Liverpool, an expert in Pseudomonas aeruginosa biology), Dr Anthony De-DeSoyza (University Newcastle, a clinician with expertise in bronchiectasis), Professor Steve Paterson (Integrative Biology, University of Liverpool, an expert in genomics and bioinformatics) and Professor Michael Brockhurst (University of Sheffield, an expert in evolutionary biology). Hence, the successful candidate will gain broad experience across a range of disciplines, including training in bioinformatics, and will interact with both clinical and non-clinical scientists.