Optimising Phage Therapy: kad and Phage-Host Dynamics in Cystic Fibrosis Lung Infections

Cystic fibrosis is the most common, genetically inherited disease in the UK and there are over 11,000 people living with this in the UK. Maintaining lung health throughout the life-course is a key priority for people with cystic fibrosis (pwCF). New modulator therapies have dramatically improved quality of life for many of this cohort. However, treatment-resistant respiratory infections still cause significant problems for pwCF of all ages, and there are some who cannot take modulators.

Lung infections are a major cause of morbidity and mortality in pwCF. Antibiotics are used extensively but antimicrobial resistance (AMR) and toxicity/side effects can increase over time. For some individuals, there are few or no treatment options left. This issue sits against a backdrop of increasing global AMR leading to reduced therapeutic options. There are few new antimicrobials in development even for microbes deemed a priority by the World Health Organisation (such as Pseudomonas aeruginosa); this is even more of an issue for CF-relevant pathogens that are less common (e.g. NTM, Burkholderia, Achromobacter, Stenotrophomonas).

The TRAILFINDER innovation hub is focused on translational innovation and is funded by the CF Trust and LifeArc as 1 of 4 hubs in the UK. The TRAILFINDER hub will address key challenges relevant to pwCF including access to the novel treatment, phage therapy.

Bacteriophage (phage) therapy is safe1 and has the potential to be relatively easily adapted across different bacterial species. Chronic lung infections in pwCF have been treated and, in some cases resolved, using phage therapy2. Phage expertise exists in the UK, however, translation to the clinic has been slow3. Globally, there have been some truly exciting case studies on the use of phage therapy in people CF4. A recent clinical trial in pwCF has been performed in the US with positive phase I/II clinical trial results for a single cocktail against P. aeruginosa5. However, case studies are limited in number and while the clinical trial is promising, there is a lack of knowledge on best practice. There is also little knowledge on the interactions of phage with other therapeutics and the lung environment in pwCF.

In this project, we will design optimised phage cocktails that are active against clinically relevant, biofilm-growing bacteria in a mucin and DNA-rich environment with altered oxygen availability. We recently showed that these factors can alter phage susceptibility however, phage treatment was also able to resensitise a pan-resistant P. aeruginosa isolate leading to successful eradication of infection from the lungs6. We will expand this work to understand the complex interactions between host environment, bacteria, phage and other therapeutics to enhance clinical efficacy. Building on our existing data, we will investigate the impact of CF-specific components of the lung environment on phage efficacy and resistance using sputum mimicking in vitro and in vivo models. Further, we will investigate the impact of polypharmacy on phage efficacy.

This PhD student will join a vibrant lab at the University of Liverpool and be part of a cohort of students, many funded by the TRAILFINDER Hub. We are committed to fostering PhD students in all aspects of development and training. The student will be based within the Dept of Clinical Infection, Microbiology and Immunology and will get the opportunity to collaborate with the wider Hub including researchers at the University of Manchester and UKHSA. Shortlisted applicants will get the opportunity to visit the laboratories and meet the wider group.

Applications should be made to Prof Jo Fothergill (j.fothergill@liv.ac.uk) and include a CV and cover letter with the subject heading “Phage PhD Application”. Candidates should have a degree in a relevant Life Sciences discipline and outline any experience that makes them the ideal candidate for the position. The applications deadline is 21/11/24.

Supervisors

Jo Fothergill – jofoth@liv.ac.uk

Aras Kadioglu – ak68@liv.ac.uk

Paul McNamara – mcnamp@liv.ac.uk

Mike Brockhurst – michael.brockhurst@manchester.ac.uk