Bacteria-phage interactions during clinical phage therapy. Biosciences, PhD (GW4 BioMed MRC DTP)

Supervisory team:
Professor Angus Buckling, Department of Biosciences, University of Exeter
Professor Sam Sheppard, University of Bath
Dr Ben Longdon, Department of Biosciences, University of Exeter
Dr Mario Recker, Department of Mathematics, University of Exeter

Project description:
With the rapid increase antibiotic resistance, alternative antimicrobials are desperately needed. Viruses that kill bacteria (phages) may be useful, but we know little about how these organisms interact during treatment. The project will involve population and genomic analysis of bacteria and phages from patients that have undergone phage therapy. 

Background:
With the rapid increase in the frequency of antibiotic-resistant bacteria, alternative antimicrobials are required. Viruses of bacteria (‘phages) may provide such an alternative. Unlike antibiotics, they have the advantage of being highly species-specific, meaning host-beneficial bacteria are not harmed during treatment. One potential limitation of phages as antimicrobials is the ease at which bacteria can evolve resistance. However, resistance often results in loss of modification of important bacterial structures, which can reduce their growth rate and virulence, and hence this may be a desirable outcome. Moreover, phages can themselves rapidly evolve to overcome resistance. Despite a wealth of data on bacteria-virus interactions in both laboratory and natural environments (the focus of Buckling’s research of the last 15 years), we currently have little knowledge of these interactions in clinical contexts. Moreover, if evolution proceeds in similar ways in vivo and in vitro, it will be possible to rapidly pre-adapt phage against target bacteria in vitro phage to increase the efficacy of phage therapy. The student will use clinical phage therapy samples (from our long term collaborators) to obtain a detailed knowledge of phenotypic and molecular bacteria-phage interactions during phage therapy. This information will be fed into mathematical models to predict treatment outcomes.

Objectives and Methods Summary:
1. To follow the evolution of bacterial resistance against therapeutic phages, and the subsequent evolution of phages to counter this resistance We already have bacteria (Pseudomonas aeruginosa) and phage clones isolated from time series samples during the treatment of more than 10 patients suffering from respiratory and blood infections. We will use standard assays to determine how bacterial resistance and phage infectivity evolves through time and other phenotypic changes. We will also sequence bacteria and phage isolates with key phenotypes through time using the Illumina HiSeq to identify likely mechanisms of resistance and infectivity. The student will extend existing statistical models quantifying bacteria-phage dynamics to control for phylogeny.
2. To experimentally coevolve the in vivo isolates in vitro To determine the similarity between in vivo and in vitro coevolution, we will use the bacterial clones isolated from patients prior to phage treatment and subsequently coevolve them with the therapeutic phage in nutrient media. Assays will be conducted as for the in vivo samples, to allow a direct comparison between the phenotypic and genetic bases of coevolution in vitro and in vivo.
3. To mathematically model bacteria-phage dynamics The student will extend existing bacteria-phage mathematical models using specific parameters from the in vitro and in vivo settings. These models will be used to explain observed variation in bacteria-phage dynamics between patients.

To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018.