MRC DiMeN Doctoral Training Partnership: Signalling systems in Pseudomonas: understanding new routes to prevent Pseudomonas aeruginosa adaptation to the lungs

Description

Background

Cystic Fibrosis (CF) is the most common genetically-inheritable life-threatening disease amongst Caucasians. People with CF are susceptible to chronic lung infections, most commonly caused by the bacterium Pseudomonas aeruginosa (Pa).  CF patients are regularly treated with aggressive antibiotic therapy, particularly during periodic pulmonary exacerbations. Antimicrobial resistance (AMR) is a global challenge, with Pa being identified by as a top priority. Understanding what drives Pa AMR is thus essential to enable the development of novel therapeutics for CF patients.

Novelty

Chronic Pa infections of the CF lung take place in a complex host and microbial environment. We have demonstrated that persister isolates of Pa from an in vivo infection model have a single point mutation in a two-component system (TCS) sensor protein kinase, pmrB, that drives both decreased expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and altered antibiotic resistance in a host environment. This mutation consequently serves as a ‘double whammy’ to promote establishment and persistence of infection. However, while we understand the phenotypic effects of this pmrB mutation on virulence and susceptibility to antibiotics, we currently have no mechanistic understanding of the drivers of this phenotype resulting from altered PmrB function. 

Timeliness

Understanding the signalling effects of PmrB in driving persistence and antimicrobial resistance is essential for successful development of anti-virulence strategies that minimise lung colonisation and improve outcomes in CF patients. Preliminary data indicates a key role for pmrB, which is only one component of over 120 TCS which remain unexplored.

This PhD project is designed as a 3.5 year project that would provide training in Pa biology, proteomics and cellular signalling as well as in vitro and in vivo models of infection, the scale of which is flexible and will depend on progress.

https://www.liverpool.ac.uk/people/jo-fothergill

https://twitter.com/JoJofoth

https://www.linkedin.com/in/jo-fothergill-017443249/?originalSubdomain=uk

https://www.liverpool.ac.uk/people/claire-eyers

https://www.liverpool.ac.uk/centre-for-proteome-research/

https://twitter.com/claireeeyers

https://www.linkedin.com/in/claire-e-eyers-7b214b14/?originalSubdomain=uk

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/