Supervisors

Lead supervisor- Professor Edze Westra, University of Exeter, Department of Bioscience

Co-Supervisor- Professor Zamin Iqbal, University of Bath, Department of Life Sciences

The GW4 BioMed2 MRC DTP is offering up to 21 funded studentships across a range of biomedical disciplines, with a start date of October 2025.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

The 120 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

 

Applications open on 10th September 2024 and close at 5.00pm on 4th November 2024.

Studentships will be 4 years full time.  Part time study is also available.

Project Information

Research Theme:

Infection, Immunity, Antimicrobial Resistance & Repair

Summary

The spread of antimicrobial resistance (AMR) is a slow-movingpandemic, identified by the WHO as atop-10 threat facing humanity. Staphylococcus aureus is an opportunistic human pathogen with high levels of antimicrobial resistance and it is a WHO priority to develop novel therapeutic solutions against this species. Phages (viruses that infect bacteria) are increasingly recognized as potential therapeutic modalities. In this project, the student will carry out large scale infection assays with diverse S. aureus isolates and phages to identify which phages are the most effective inhibitors of S. aureus growth, and tease apart why this is the case.

Project description

The spread of antimicrobial resistance (AMR) is a slow-moving pandemic and has been identified by the WHO as one of the top 10 threats facing humanity. Mobile genetic elements (MGEs), such as phages and plasmids, play a key role in AMR dissemination but also offer a promising basis for non-antibiotic therapies. The activity of MGEs is fundamentally shaped by bacterial defenses, which can suppress AMR spread and limit the efficacy of phage-based therapies. Well-known bacterial defenses include Restriction-Modification (RM) and CRISPR-Cas, but it is now recognized that bacteria carry more than 100 defense systems. These defenses act at different stages of the MGE lifecycle: some cleave MGE genomes immediately following infection, others interfere with MGE transcription or replication, or induce cell death or dormancy responses. Large-scale systematic studies are necessary to develop a broader understanding of how these defenses integrate and shape bacteriaphage interactions, which is essential to outflank AMR. We predict that bacterial defenses can interact synergistically or antagonistically, and that such combinations occur more and less frequently than expected by chance, respectively. To identify interactions supporting this hypothesis, we will identify known defense genes in publicly available whole genome sequences and analyze their co-occurrence patterns using phylogenetically controlled models.

Next, we will use a diverse collection of over 500 sequenced S. aureus isolates that differ in geographical, clinical origin, ecology and host. Using bioinformatics pipelines, we will build phylogenies, and identify known defense genes in these isolates. On these 500 isolates, we will perform large-scale infection assays using a panel of 15 phages that can infect S. aureus. This panel captures diverse phage families with distinct life styles, genome sizes, and replication mechanisms, allowing us to test whether certain defenses are specific to particular phage types and whether combinations of defenses provide complementary or overlapping resistance ranges.

Our team has recently developed high-throughput analyses of phage resistance and infectivity based on OD600 plate reader assays, which will be adopted in this project. We will analyze the resulting infectivity/resistance data using phylogenetically controlled statistical models to examine how defense types and combinations correlate with phage resistance phenotypes, and to what extent this depends on the phage type. The correlational analysis will highlight certain defense combinations that provide synergistic levels or broader ranges of resistance.

To test for causality, we will express defense genes individually or in combination in S. aureus lab strains. The bioinformatics analysis may also point towards combinations observed less frequently than expected, suggesting potential antagonistic interactions. Strains with such combinations can be engineered by combining the respective constructs. Using the same approaches, we will test how individual defenses and their combinations impact phage infectivity. Finally, we will select individual defenses and synergistic combinations for follow-up bulk infection experiments to gain deeper insights into the consequences for bacterial and phage population dynamics. These experiments will also reveal whether phage can evolve to overcome defenses, and how this depends on the combinations of defenses in the host bacteria. We will identify phage mutants that evolved to overcome host defenses by comparing their infectivity against that of the ancestral phage. Where increases in infectivity are observed, we will perform Illumina sequencing to identify the genetic basis.

We expect that in some cases, phage resistance or infectivity patterns cannot be explained by known defense genes, suggesting the presence of unknown defenses. To identify these, we will apply our recently developed Tn mutagenesis assays (Maestri et al Cell Host Microbe 2024) where a Tn library is infected with selective or fluorescent markerlabelled temperate phage that poorly infect the ancestral WT genotype of the isolate. Selective plating or FACS sorting of lysogens (i.e. bacteria infected with the temperate phage, which integrate into the genome) followed by Tn-seq will enable the identification of defense genes. The applicant will benefit from being embedded in a dynamics and prolific team of researchers who study bacteria-phage interactions, as
well as being embedded in the BBSRC sLoLa Multidefence network (https://sites.exeter.ac.uk/multidefence/) and the BBSRC Mission Award "Safephage" network.

Key publications from supervisory team related to the project: Bacteriostatic antibiotics promote CRISPR-Cas adaptive immunity by enabling increased spacer acquisition. Dimitriu T et al Cell Host Microbe. 2022
Exploitation of the Cooperative Behaviors of Anti-CRISPR Phages. Chevallereau A et Cell Host Microbe. 2020
Targeting of temperate phages drives loss of type I CRISPR-Cas systems. Rollie C, et al Nature. 2020
Bacterial biodiversity drives the evolution of CRISPR-based phage resistance. Alseth EO et al Nature. 2019
Ultrafast search of all deposited bacterial and viral genomic data. Bradley P, et al Nature Biotech 2019
Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity. Landsberger M et Cell. 2018 The diversity-generating benefits of a prokaryotic adaptive immune system. Van Houte S, et al Nature. 2016
Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus andMycobacterium tuberculosis. Bradley P Nat Commun. 2015.

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£19,237 p.a. for 2024/25, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 4th November 2024.  If you are shortlisted for interview, you will be notified from Friday, 20th December 2024.  Interviews will be held virtually on 23rd and 24th January 2025.

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary