BBSRC Wessex One Health (WOH) Doctoral Landscape Award

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Understanding Disease Spread; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Elizabeth Mumford, e.mumford@surrey.ac.uk

Joint partner: APHA 
Supervisor: Emma Snary, Emma.snary@apha.gov.uk

Collaborative partner: University of Sussex

Project Summary

One Health (OH) aims to address complex health challenges (e.g. zoonotic diseases, AMR) by improving multisectoral collaboration. Systems Thinking methodologies address complex systems in social science, engineering, and public health contexts but have not been applied in mainstream OH contexts, potentially limiting OH’s impacts and sustainability.  Our consortium is working to improve OH outcomes by broadening the methodological and cultural OH paradigm globally. Activities include developing a dynamic ‘Process Schema’ framework to support OH users in applying Systems Thinking (https://openresearch.surrey.ac.uk/esploro/project/research/Enhancing-One-Health-Through-Systems-Thinking/12834656450002346), for example, to guide application of a participatory, systems approach to understand the complex socioecological system contributing to rabies virus transmission among dogs, bats, and humans and impacting community health and wellbeing.

Within this overall initiative, objectives for the proposed studentship are to: 

1. Identify Systems Thinking and other methods appropriate to understanding and managing complex OH challenges
2. Integrate these methods into the draft Schema
3. Test by applying selected methods to a complex OH challenge 

The student will undertake a literature review and deep dive interviews with experts (e.g. from APHA/DEFRA) to understand methods for approaching complex systems, including when and for what they are used and impact. They will integrate their findings into the Schema and test the methods in complex health contexts in the field, e.g. our EU-PAHW project investigating environmental and climate change impacts on bat/Lyssavirus ecology, building on APHA’s surveillance data and modelling activities.

This project is critical to understanding the methodological options available, how they are used, and their impacts. This is a requirement for further Schema development and directly impacts our capacity to undertake subsequent steps to influence the aspired OH paradigm shift. Although the methods are not new, their application in OH contexts is innovative and critical to address threats such as emerging zoonotic diseases and AMR and evolve OH globally.  

Theme(s): Detection, Prevention and Intervention; Understanding Disease Spread

Lead partner: University of Surrey 
Supervisor: Kevin Wells; k.wells@surrey.ac.uk

Joint partner: APHA 
Supervisor: Alexander Mastin, Alexander.mastin@apha.gov.uk

Project Summary

The global threat of viruses such as high pathogenicity avian influenza (HPAIV) impacts both bird/animal populations and raises risks of transmission to humans. Commercial incursions of HPAIVs result in culling with resultant economic losses impacting the farming community. HPAIV also severely affects wild bird populations, with potential major conservation impacts. The zoonotic threat from HPAIV is significant with influenza generally considered the potential next true global pandemic. 

Protecting livestock from diseases like HPAI requires early detection and rapid response. Government-led responses are essential to disease control but understanding the human factors that influence virus spread is critical for the evolution of policy decisions. This requires multidisciplinary work involving a vast array of stakeholders. Decision makers’ engagement with stakeholders is primarily with selected representatives from the livestock industry. However, using AI to interrogate online resources offers a valuable alternative source of information on risk definition. 

The DataHub group at Surrey has world leading expertise in using artificial intelligence (AI) to identify on-line conversations, influencers, their connections and sources of (mis)information. Trawling social media using AI offers a novel opportunity to enhance perceptions of disease. AI assessment of social media will inform changes in communications pathways and hence guide future responses and define gaps in public perception of disease to optimise reactive responses. Further, human responses to infection following detection of cases will be assessed to define biosecurity messaging and zoonotic risk factors. We will seek to understand the on-line connectivity of various avian stakeholders, the key influencers and opinion formers, their network connections and attitudes within different on-line groups and their communications across these different segments of various on-line communities.

We are seeking an enthusiastic PhD candidate with a numerate degree, including coding and data science skills, ideally with relevance to epidemiology and/or biological modelling to pursue this exciting opportunity.

Theme(s): Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: David J Allen, d.j.allen@surrey.ac.uk

Joint partner: APHA 
Supervisor: Alex Stewart, alex.stewart@apha.gov.uk

Project Summary

Virus infections of pigs have a global economic impact of billions of dollars annually. Alongside affecting animal health directly, they cause secondary bacterial coinfections driving antibiotic use, contributing to AMR, and indirectly affect human health through impacting food security and livelihoods through losses. Endemic and emerging viruses in pig populations include flaviviruses, picornaviruses, nidoviruses and parvoviruses.

Understanding virus-host interactions such as immune responses mediated by type-I interferons (IFN-I) that initiate antiviral responses are underexplored as pathways to developing countermeasures. 

Early virus-host interactions do not occur in isolation: sites targeted by viruses have populations of resident commensal bacteria (‘microbiota’) which can modulate immune responses. Lactic acid bacteria (LAB) – common beneficial commensals – activate IFN-I responses via intracellular sensors STING and MAVS which are important components of signalling systems that initiate IFN-I antiviral responses to DNA and RNA viruses, respectively.

Therefore: can LAB trigger an antiviral response for therapeutic use?

The project will answer this question through three objectives:

1. Build cell-based laboratory models for measuring IFN-I responses following infection with RNA/DNA viruses, in the presence/absence of LAB, and with/without STING or MAVS.
2. Determine components of LAB critical for the activation of STING or MAVS, and characterise IFN-antagonistic viral proteins in these systems.
3. Test LAB – or LAB components – against a panel of viruses to demonstrate their potential as a therapeutic.

The project provides training in laboratory techniques, including CRISPR, RNA knockdown/out, stable cell line production, molecular biology, quantitative RT-PCR, sequencing, protein-protein interaction assays, bacterial culture, recombinant protein expression, cell transfection, and virus/cell culture, and working with APHA who have collections of porcine viruses for study in laboratory and in vivo challenge systems.This one-health research will establish potential for use of LAB as a probiotic, and/or identify components of LAB for development as therapeutics, to control viral infections in pig herds.

Theme(s): Detection, Prevention and Intervention, Understanding Disease Spread, Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Graham Stewart, g.stewart@surrey.ac.uk

Joint partner: APHA 
Supervisor: Daryan Kaveh, daryan.kaveh@apha.gov.uk

Project Summary

Mycobacterium bovis is the causative agent of bovine tuberculosis (bTB) and the predominant cause of zoonotic tuberculosis worldwide. In the UK and Ireland, control of bTB is complicated by a reservoir of infection in badgers. Transmission between badgers and cattle (and vice versa) is not well understood but may involve an environmental step between hosts. We hypothesise that interaction with environmental amoebae increases infectivity of M. bovis. In preliminary experiments to support this PhD project we showed that M. bovis actively escapes predation by the soil and dung-dwelling amoeba, Dictyostelium discoideum (Butler et al 2020). It does this using the ESX-1 and ESX-5b type VII secretion systems as part of an extensive programme of mechanisms involving hundreds of genes.

In this project, the student will characterise how M. bovis changes its physiology during infection of Dictyostelium and establish if these changes pre-adapt the bacterium for mammalian infection, as is the case for other bacterial pathogens such as Legionella pneumophila, Vibrio cholerae and Salmonella enterica. Indeed, for Legionella the demonstration that passage through amoebae increased infectivity was critical to understanding the paradox that concentrations of Legionella below the experimentally determined infective dose were able to cause human infection. Thus, it is important that we understand the effect of amoeba passage on M. bovis physiology and how this affects infectivity. This fundamental biology could transform our understanding of bTB transmission and will help design measures to control environmental transmission of M. bovis. Specifically, the findings will guide validation of disinfection strategies for bTB breakdown farms with the potential to significantly impact persistence rates and infection of reintroduced cattle.

Butler, RE, Smith, AA, Mendum, TA, Chandran A, Wu H, Lefrançois L, Chambers M, Soldati T and Stewart GR. (2020) Mycobacterium bovis uses the ESX-1 Type VII secretion system to escape predation by the soil-dwelling amoeba Dictyostelium discoideum. ISME J doi:10.1038/s41396-019-0572-z

Theme(s): Understanding Disease Spread

Lead partner: University of Surrey 
Supervisor: Joaquin Prada, j.prada@surrey.ac.uk

Joint partner: DSTL 
Supervisor: Joe Gillard, JGILLARD@dstl.gov.uk

Collaborative partner: APHA

Project Summary

The recent SARS-CoV-2 global pandemic has highlighted the need to improve surveillance for new and emerging threats and improved preparedness in critical sectors. For instance, in a military context, effective infection control measures are essential to ensure that operations can continue. This is particularly challenging when a new respiratory infection emerges, for example through a zoonotic reservoir, with direct human-to-human transmission potential and asymptomatic carriers that might delay detection. This project aims to develop general methodologies and evaluate these risks in an illustrative set of scenarios, combining stakeholder elicitation techniques, transmission dynamics modelling integrating biology with mathematics and statistics. This will be tackled through the following objectives:

Objective 1: Identify a set of representative scenarios through a Multi-Decision Criteria Analysis evaluation exercise with subject matter experts (e.g. military advisors, One Health professionals) and elicit criteria for operational effectiveness in each setting. 

Objective 2: Characterize contact points for transmission, identify suitable diagnostic surveillance approaches, and explore the impact of different interventions in these scenarios using a disease dynamics mathematical modelling framework. 

Objective 3: Assess the expected changes in operational effectiveness by integrating model outcomes with the key criteria for success in each scenario.

The student will acquire broad and valuable expertise in mathematical modelling, Operational Research and infectious diseases, through this unique collaboration between UoS, Dstl and APHA. By exploring scenarios for a new “Disease X” epidemic of potential zoonotic origin, the student will be at the cutting edge of interdisciplinary research in this area. Outcomes from the project will provide key stakeholders (e.g. the military community, the agriculture sector, outbreak response teams) with evidence to support decision-making about potential risks and mitigation strategies in operational environments. The student will thus deliver a novel framework for the holistic assessment of challenges from emerging respiratory pathogens to the defence sector and beyond.

Theme(s): Understanding Disease Spread

Lead partner: University of Surrey 
Supervisor: Richard Sear, r.sear@surrey.ac.uk

Joint partner: DSTL 
Supervisor:  Richard Thomas, rjthomas@mail.dstl.gov.uk

Collaborative partner: University of Bristol

Project Summary

Understanding virus survival in the environment is an important problem in public health, and in defence & security. A virus must survive its journey in our environment from one host to the next, and so survival is key to virus transmission. When a respiratory virus, such as influenza, respiratory syncytial virus (RSV) or coronavirus, is breathed out it leaves the host’s airways in tiny droplets - as a bioaerosol. These bioaerosols can fall onto surfaces, and later infect a new host.

It is impossible to study every possible virus surviving or not on every possible surface, so we need general mechanistic insights, and this is the aim of this PhD project. We aim for the results to give general practical guidance on transmission risk for both current and emergent infectious diseases. Mechanistic understanding supports translation between viruses, different surfaces and decontamination regimes, enabling informed guidance. 

The project will address key questions such as: How does bioaerosol size affect survival probability or lifetime? Does the interaction of bioaerosol particles with surfaces affect decontamination practices? Surprisingly, even though infectious viruses are a huge burden worldwide, the answers to these basic questions are unknown. The PhD project is both highly interdisciplinary, and combines fundamental science with real world applications.

We will use respiratory syncytial virus (RSV) as a model organism. RSV is an enveloped virus responsible for approximately 3.4 million hospitalisations and 100,000 deaths worldwide each year. RSV primarily causes severe disease in young children and older adults.

The bioaerosols will be studied using the state-of-the-art Controlled Electrodynamic Levitation and Extraction of Bioaerosol onto Substrate (CELEBS) system, developed by our collaborators at the University of Bristol. Bioaerosol composition, droplet size, and drying rate, will be varied with surface aspects such as material type (e.g. metal, fabric) and surface roughness

Virus viability will be quantified by cell-based infection assays. Membrane integrity, protein denaturation and genomic integrity will enable detailed assessment of how physical factors in a drying aerosol inactivate viruses.

Theme(s): Understanding Disease Spread

Lead partner: University of Surrey 
Supervisor: Klara Wanelik, k.wanelik@surrey.ac.uk

Joint partner: DSTL 
Supervisor: Thomas Laws, trlaws@mail.dstl.gov.uk

Project Summary

Superspreaders are the minority of individuals responsible for the majority of disease spread and come in two forms. Supershedders spread more disease because they shed more pathogen. Supercontacters spread more disease because they have more social contacts. The presence of supershedders and/or supercontacters in a population is likely to be associated with distinctive patterns of disease spread which, if detected early, could be used to better design disease control strategies.

In this project, you will use a novel epidemiological modelling approach to simulate disease outbreaks in closed populations (representative of e.g. a military base or naval vessel) and to better understand the role of supershedders and/or supercontacters in driving patterns of disease spread. Your model will incorporate both within-host and between-host dynamics.

Project objectives: 

1. In a scenario where there are only supershedders, identify which physiological features of supershedders (e.g. infectious period, pathogen load) impact on patterns of disease spread and how.
2. In a scenario where there are only supercontacters, identify which behavioural features of supercontacters (e.g. contact frequency, contact duration, contact heterogeneity) impact on patterns of disease spread and how.
3. In a more realistic scenario where there are supershedders and supercontacters, identify which features of supershedders and supercontacters impact on patterns of disease spread and how.

You will use openly available datasets for a representative range of viral pathogens to parameterise and test your model. This will include Ebola and Lassa virus – two major pathogens of strategic importance that exhibit contrasting dynamics. 

This project is an exciting opportunity to contribute to preparedness for pathogen X, a pandemic pathogen that has not yet been characterised. It would suit those with an interest in infectious diseases, public health and/or epidemiological modelling. Experience in epidemiological modelling is desirable but not essential. The individual will work closely with Dstl.

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Understanding Disease Spread

Lead partner: University of Surrey 
Supervisor: Bingxin Lu, b.lu@surrey.ac.uk

Joint partner: Pirbright Institute 
Supervisor: Tim Downing, Tim.Downing@pirbright.ac.uk

Project Summary

Poxviruses pose a major threat to human and livestock health, such as mpox, which remains a continuing threat. Poxviruses evolve through a combination of mutation, recombination, and gene transfer. These processes permit the exchange of new DNA segments, which may encode proteins with novel functions in new viral hosts, resulting in new outbreaks and epidemic threats. Moreover, high rates of rearrangements and repetitiveness in poxvirus genomes obscure the adaptation and origins of different lineages. Existing tools to study these processes were developed for prokaryotic or eukaryotic organisms and certain virus types, but none have been optimised for poxviruses. Additionally, we are now in a much better position to understand poxvirus adaptation, thanks to recent advances in extensive short- and long-read genome sequencing of human and livestock poxviruses. This means new inferences are possible, if appropriate scientific methods are used.

This project will explore published diverse poxvirus genomes using better gene transfer and recombination analysis. It will leverage two novel approaches: pangenome graphs and artificial intelligence-informed phylogenetics. We will use unsupervised machine learning methods based on DNA similarity and related pangenome graph information to identify regions of interest in individual virus genomes. This will be designed to identify gene transfer and recombination in new, unknown samples. Identified gene transfer and recombination events will be verified using phylogenetic methods and compared to the results of existing tools to validate and improve the new approaches.

This project will train you in cutting-edge methods (machine learning, genomics/pangenomics, and viral genetics) that will shed new light on gene transfer, recombination, and genomic diversity in poxviruses. It will create improved genome analysis methods for poxviruses to pin-point genes driving outbreaks with pandemic potential. This project will lay a foundation on which to explore virus evolution, and to apply these machine-learning and pangenomic tools to other viruses.

Theme(s): Detection, Prevention and Intervention; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Paola Campagnolo, p.campagnolo@surrey.ac.uk

Joint partner: The Pirbright Institute 
Supervisor: Kevin Maringer, Kevin.Maringer@pirbright.ac.uk

Project Summary

Microvascular dysfunction plays a key role in the pathogenesis of many haemorrhagic viral diseases, offering new opportunities for broad-spectrum diagnostics and therapies. In our MRC-funded study, we identified Protein X (patent pending) as a novel soluble mediator of microvascular dysfunction, using dengue haemorrhagic fever as a model. Produced by perivascular cells (pericytes), Protein X disrupts endothelial function, leading to hyperpermeability. Protein X has both a functional role in mediating dengue haemorrhage and a prognostic value in the stratification of infected patients that may develop severe symptoms.

This project aims to further investigate Protein X’s role in microvascular dysfunction and its potential as a diagnostic and therapeutic target for viral infections in humans and livestock. The student will gain expertise in proteomics, molecular virology, 2D/3D vascular co-culture models, imaging, and nanomedicine. The project has three main objectives:

1. Conservation of Protein X mechanisms across species and viruses: Leveraging Pirbright CL3 facilities, the student will challenge various livestock cell lines with haemorrhagic viruses to explore whether Protein X-mediated endothelial dysfunction mechanisms are conserved across species/viruses.
2. Elucidate the mechanisms of Protein X-dependent endothelial dysfunction: Our RNAseq data suggests that Protein X affects several pathways in human endothelial cells. The student will conduct functional/molecular assays to identify molecular players involved in Protein X-driven haemorrhage.
3. Deliver proof-of-concept data towards the development of bedside test for Protein X: In collaboration with Dr. Michael Thomas (UCL), and with the support of the Pirbright’s expertise in lateral flow assay (LFA), the student will drive the early development of a lateral flow testing device for Protein X based on the ProImmune’s Ankyron technology (animal-free antibody alternatives). These results will provide the initial steps towards enabling bedside patient stratification.

This project combines mechanistic insights with new diagnostic tools, offering the potential to improve the standard of care for patients and livestock affected by viral infections, with significant impacts on human health, livestock health, and food security.

Theme(s): Detection, Prevention and Intervention

Lead partner: University of Surrey 
Supervisor: Patrizia Camelliti, p.camelliti@surrey.ac.uk

Joint partner: Pirbright Institute  
Supervisor: Wilhelm Gerner; wilhelm.gerner@pirbright.ac.uk

Project Summary

Global supplies of pork are threatened by African swine fever (ASF), a devastating disease of pigs and wild boar. ASF virus (ASFV) targets macrophages and replicates in lymphoid organs such as the spleen. Despite its importance for the development of ASF vaccines and ASF resilient animals, research on host ASFV interactions has predominantly focused on 2D macrophage cultures, which fail to capture the heterogeneity of immune processes during infection. Cutting-edge 3D cultures more closely represent in vivo conditions compared to 2D cultures, enabling the investigation of multifaceted cell-cell and cellpathogen interactions within host tissues. Moreover, 3D cultures provide a tractable model system that reduces the use of animals in research. This interdisciplinary project aims to develop a porcine spleen derived 3D model from waste tissues using bioengineering and immunology techniques to study the complex host immune responses and cellular interactions during ASFV infection. Organotypic slices prepared from freshly isolated spleen and 3D spheroids generated using spleen derived cells will be explored to identify the model system that is best suited to study porcine innate immunity. Cellular composition, longevity, stability and innate immune responses to stimulants will be compared to existing 2D model systems and in vivo data. Established 3D models will then be used to study the differential host immune processes and immune cell dynamics modulated by ASFV strains of varying virulence. Importantly, this work will develop a novel, sustainable and ethically responsible 3D spleen model platform for use in host-pathogen research as well as related fields such as disease modelling and pharmacology, with applications spanning both veterinary and biomedical research domains. Furthermore, this project will provide a novel perspective on host immune responses to ASFV infection and potentially identify immune mechanisms leading to the development of future ASF control strategies to improve livestock health and global food security.

Theme(s): Detection, Prevention and Intervention; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Anjan Dutta, anjan.dutta@surrey.ac.uk

Joint partner: Pirbright Institute 
Supervisor: Ryan Waters, ryan.waters@pirbright.ac.uk

Project Summary

Zoonotic pathogens pose a threat to global health, risking widespread outbreaks in humans and animals. Early detection in livestock and wildlife is crucial but hindered by labour-intensive, delayed diagnostic techniques. Advancements in artificial intelligence (AI) can transform disease monitoring and intervention. However, developing such AI models requires large volumes of annotated data that poses a bottleneck, because annotating high-quality datasets is particularly challenging due to logistical, ecological, and financial constraints. This project addresses these issues by leveraging large foundation models, like large language models (LLMs) and vision-language models (VLMs), pre-trained on billions of data points, enabling predictions from multimodal information (Qu et al., 2024).

This project will develop AI algorithms to analyse livestock images and videos for infection signs, such as behavioural changes, physical abnormalities, and thermal anomalies. Models will integrate data from multimodal sources, including video feeds, thermal cameras, accelerometers, and environmental sensors from farms (Hatton et al., 2015) or simulated animal facilities at the Pirbright. For wildlife, computer vision systems using drone-mounted video feeds and camera traps will monitor behaviours, migration patterns, and interspecies interactions (Swanson et al., 2015). Spatiotemporal data analysed with machine learning will identify disease transmission hotspots (Ng et al., 2022). Insights from livestock and wildlife will provide real-time alerts for targeted interventions. Field trials will validate the system’s scalability and performance.

The proposed project has transformative potential to mitigate the impacts of zoonotic diseases, saving up to £29 billion annually by reducing outbreak costs (World Bank, 2012). It can enhance livestock productivity by lowering disease-induced losses by 10-15% (FAO, 2020) and support wildlife conservation by decreasing species mortality by 15-20% (IUCN, 2021). By reducing zoonotic spillovers by 10-20%, it safeguards public health (WHO, 2018). Scalable deployment could benefit 500,000 farms and 10,000 conservation areas, revolutionising global disease monitoring and intervention strategies (OIE, 2020).

Theme(s): Microbial Evolution and Drug Resistance; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Dr Jai Mehat, jw.mehat@surrey.ac.uk

Joint partner: Pirbright Institute  
Supervisor: Erica Bickerton, erica.bickerton@pirbright.ac.uk

Project Summary

The University of Surrey, in collaboration with The Pirbright Institute, are offering an exciting PhD opportunity to investigate the complex interplay between avian coronavirus infectious bronchitis virus (IBV) and Avian Pathogenic Escherichia coli (APEC) in poultry. Project Background and Rationale The poultry industry is vital for feeding a growing global population but faces significant challenges from infectious diseases. Co-infections with IBV and APEC represent a major threat, causing immune suppression and secondary infections that lead to systemic colibacillosis and economic losses. Despite available vaccines, their efficacy is limited due to narrow strain coverage and a lack of understanding of how IBV predisposes poultry to opportunistic APEC infections. This project aims to close this knowledge gap by exploring the mechanisms through which IBV enhances APEC colonisation, bacterial opportunism, and identify viral and bacterial strain combinations that lead to the most severe disease outcomes. Approaches This project aims to unravel the cooperative dynamics of IBV and APEC co-infections. We will use cutting-edge in vitro and ex vivo models to investigate IBV-APEC interactions in the avian respiratory tract (RT), and establish the basis by which IBV may augment colonisation of the RT by diverse strains of APEC. High-resolution metagenomics will be employed to study IBV-induced microbiota changes that may promote APEC shedding from the chicken gut. Impact and Career Opportunities This PhD offers the unique benefit of collaboration between the University of Surrey and The Pirbright Institute, creating a rich learning environment that bridges academic and applied science. This research will provide critical insights into viral-bacterial co-infections- a key challenge in One-Health contexts, paving the way for improved disease control strategies and reducing reliance on antimicrobials.

Theme(s): Understanding Disease Spread; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Matteo Barberis, m.barberis@surrey.ac.uk

Joint partner: The Pirbright Institute 
Supervisor: Naomi Forrester-Soto, Naomi.forrester-soto@pirbright.ac.uk

Project Summary

This project aims at gaining systematic and mechanistic insights into viral infections. Specifically, it is designed to understand the metabolic and proteomic response of persistent infections in mosquitoes through a Systems Biology strategy that integrates multiple levels of –omics data with experimentation. Viruses that use invertebrates as part of their lifecycle include well-known viruses such as Dengue virus, Chikungunya virus, and Yellow fever virus. Persistent viral infections do not result in pathological injury to their hosts, but the presence of the infection causes a metabolic burden, which can impact the host. This interaction is not well understood. However, we know that successful infection of mosquitoes is multi-factorial and the mosquito metabolism is an understudied aspect of this interaction. Our hypothesis is that mosquito metabolism, and its regulation from the proteome, is critical to sustaining persistent infections and that specific metabolites can be identified that provide an environment allowing for viral persistence. The student will utilise a series of mutant viruses from highly attenuated to wild-type that will enable us to interrogate the role of metabolism in determining whether the virus is able to establish a persistent infection. They will use a combination of in vitro and in silico approaches to generate and prepare samples for metabolomic and proteomic analyses, using the wild-type and mutant strains of Venezuelan equine encephalitis virus (VEEV). The metabolomic and proteomic data will be integrated and annotated onto biochemical maps, which will be analysed to identify metabolic/proteomic targets in different states of viral infection. The results will be verified by targeting some of these key targets as indicators during viral infections and testing the outcomes for various viruses. Outcomes from this project will help us understand the relationship between mosquitoes and persistent viruses, and will inform novel targeting strategies for the control of important mosquito-borne viruses.

Theme(s): Infection and Cellular Biology; Detection, Prevention and Intervention

Lead partner: University of Surrey 
Supervisor: Salvatore Santamaria, s.santamaria@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Anika Singanayagam, Anika.Singanayagam@ukhsa.gov.uk

Project Summary

Upper respiratory tract infections are the leading cause of acute disease worldwide with over 12 billion incidents a year. Respiratory viruses including influenza and respiratory syncytial virus (RSV) circulate seasonally and are associated with significant morbidity and mortality. Current prevention (vaccines) and intervention strategies (antivirals) are focused exclusively on the virus but are only moderately effective. An area that has been largely ignored in the quest for new treatments is the impact of host responses on disease severity and eventual outcome. Extracellular matrix (ECM)-associated metalloproteinases called ADAMTSs were recently discovered to contribute to virus immunity and disease outcomes. Mice bearing a deletion in the gene coding for ADAMTS5 are protected from severe influenza infection, while those lacking ADAMTS4 showed improved survival. However, the mechanisms behind these phenotypes are not elucidated.

We hypothesise that pharmacologic inhibition of ADAMTS4 may improve survival after lung viral infection, while increasing ADAMTS5 levels may improve survival. By using selective anti-ADAMTS4 and ADAMTS5 monoclonal antibodies (mAbs), we will assess the contribution of these proteases to viral lung infections in cell-based systems. Eventually, these studies will pave the way for future preclinical/clinical applications.

We have already generated 1) a mAb blocking ADAMTS4 activity; 2) a mAb that increases extracellular ADAMTS5 levels by blocking ADAMTS5 internalisation into the cells and subsequent degradation. We have showed the efficacy of these mAbs in ex-vivo models of osteoarthritis. In this project, we aim to repurpose anti-ADAMTS mAbs and assess their feasibility as treatments for viral lung infections by achieving three specific aims:

1. Reformatting, expression and purification of humanised anti-ADAMTS and anti-ADAMTS5 mAbs.
2. Assessing the effect of anti-ADAMTS mAbs on cell lines and primary cells infected with RSV and influenza virus.
3. Understanding the impact of ADAMTS mAbs on the innate immune responses to respiratory viral  infection and subsequent disease.

Theme(s): Detection, Prevention and Intervention

Lead partner: University of Surrey 
Supervisor: Carol Crean, c.crean@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Charlotte Hind, charlotte.hind@ukhsa.gov.uk

Project Summary

Anti-microbial resistance (AMR) remains one of the greatest threats to humanity. Chronic wounds are wounds that fail to show a timely improvement during treatment and those that exceed a 3-month healing process. Wound infection and its persistence are widely considered a major contributor to chronicity, with bacterial biofilms being responsible for over 80% of persistent infections and with many exhibiting genetic AMR.

As they grow, bacteria produce a variety of enzymes, which has led to the development of enzyme inhibitors for bactericidal effects. β-lactam antibiotics have been widely used; however, bacteria have evolved to produce antibiotic inactivating enzymes, such as β-lactamases. β-Lactamases hydrolyse the β-lactam ring before this class of antibiotics can kill its target bacteria. β-lactamases are the leading cause of antibiotic resistance to key front-line antibiotics such as penicillins and cephalosporins.

Methods currently used to detect β-lactamases include culture-based or molecular methods, which are expensive and time-consuming. This project aims to use electrochemical sensors to rapidly measure β- lactamase enzymes in wound models. The goal is to develop sensors for use in diagnosing infection (in collaboration with UKHSA). The sensors will be flexible and conform to the skin and will use textile-based electrodes. The sensors will be used to monitor β- lactamase enzymes using bacterial strains plus and minus the beta-lactamase enzyme.

The wearable sensors developed will allow early detection of drug-resistant infection in wounds. This is important in terms of minimising the use of antibiotics and preventing antibiotic misuse. Alternative enzyme targets, such as aminopeptidases that are indicative of different bacterial and fungal pathogens, may also be explored as part of the study. This project aligns with the UK's second 5-year AMR National Action Plan (2024 to 2029), in terms of Outcome 5; diagnostics for infection management and Outcome 6; innovation and influence.

Theme(s): Detection, Prevention, and Intervention, Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Dany Beste, D.beste@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Joanna Bacon, Joanna.bacon@ukhsa.gov.uk

Project Summary

Introduction

Infections caused by non-tuberculous mycobacteria are increasing globally leading to significant morbidity and mortality. Amongst these lung infections with M. abscessus cause the greatest morbidity and mortality in people with chronic respiratory diseases (COPD, cystic fibrosis and bronchiectasis). Antibiotic treatment is extremely challenging and requires a cocktail of antibiotics taken for months to years and frequently fails to irradicate the infection. 

Bacterial metabolism is a bone fide therapeutic target for the development of new antibiotics, but we know little about the metabolic pathways that sustain M. abscessus during infection. Propionate accumulates in the lungs of people with cystic fibrosis at millimolar concentrations. Propionate is immunomodulatory and toxic to bacterial cells and blocking propionate metabolism in several pathogens reduces virulence and kills bacteria. However, propionate metabolism remains unexplored in M. abscessus. This PhD research project will address this knowledge gap and elucidate the metabolic pathways used by M. abscessus to metabolise propionate in host relevant conditions.

Approach

Our hypothesis is that propionate metabolism is critical to the lifecycle of M. abscessus. To test this the student will perform mutagenic, metabolic, and bacterial cell culture/infection-based assays to identify the pathways and enzymes involved. By applying a combination of omics this project will provide systems-level insight into propionate metabolism by M. abscessus. Optimised models that mimic lung conditions will be used to screen drug libraries and discover novel antibiotics against M. abscessus. 

Impact. This PhD project is a collaboration between the University of Surrey and UKHSA Porton Down and therefore bridges academic and public health research. The results from these studies will lead to a fundamental understanding of metabolism in M. abscessus and identify drug targets that can be translated into interventions for patients and therefore contribute to the UK AMR National Action plan.

Theme(s): Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Lisa Holbrook, l.holbrook@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Stuart Dowall, stuart.dowall@ukhsa.gov.uk 

Collaborative partner: The Pirbright Institute

Project summary

Rift Valley fever virus (RVFV) is a mosquito-transmitted, zoonotic, emerging bunyavirus categorised by WHO as a high-consequence, priority pathogen due to its emergence and lack of effective and safe antiviral treatments. It causes viral haemorrhagic fever in humans and livestock characterised by necrotic lesions in major organs, thrombocytopenia (low platelet numbers), coagulation defects as well as increased vascular permeability resulting in oedema, hypotension, shock, and death. How RVFV induces pathology remains largely unknown and understanding the molecular and immune mechanisms underlying RVFV pathology will identify new avenues for therapeutics development.

Viruses associated with haemorrhagic fever cause destruction or dysfunction of platelets, leading to thrombocytopenia. Platelets are essential in haemostasis, for integrity of the vascular system and immunity. They can be activated aberrantly by interaction with viruses or virus-infected cells. Activated platelets adhere to endothelial cells, thereby reducing the number of circulating platelets, altering endothelial cell function, and increasing vascular permeability. In this project we hypothesise that RVFV activates platelets which induces thrombocytopenia. Treatments that prevent or correct platelet loss and dysfunction in RVFV infection have the potential to ameliorate platelet-mediated pathology and to significantly improve clinical outcome. Additionally, platelets secrete redox proteins (thiol isomerases) which conversely enable virus entry and fusion, therefore thiol isomerases may also contribute to RVFV pathogenesis.

This project will examine the molecular and immune interactions between RVFV and platelets leading to pathology by characterising the mode of RVFV-induced platelet activation and thrombocytopenia using a combination of in vitro and in vivo methods. Confirmation of in vitro mechanisms will be evaluated using material from RVFV challenge animal models allowing comparison with disease severity. Platelet redox changes as both a marker of platelet function and, additionally as a potential facilitator of RVFV infection will also be explored in both the vitro and in vivo models of RVFV infection.

Theme(s): Detection, Prevention and Intervention

Lead partner: University of Surrey 
Supervisor: Suzie Hingley-Wilson, s.hingley-wilson@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Ginny Moore, ginny.moore@ukhsa.gov.uk

CASE partner: Vidiia: Vidiia

Project Summary

Tuberculosis (TB) is often called the forgotten pandemic, causing over 1.3 million deaths every year. Much of this burden is in West Africa, where many of the TB-causing strains are not the usual suspect Mycobacterium tuberculosis (Mtb). Up to 50% of TB cases may be misdiagnosed, with many caused by other lineages of the Mycobacterium tuberculosis complex (MTBC) or by non-tuberculous mycobacteria (NTM), such as Mycobacterium abscessus (MABC). Research from our lab also revealed a high proportion of mixed MTBC infections and potential nontuberculous mycobacteria (NTM) causing TB (Owusu et al., 2022). Treatment for Mtb, MTBCs and NTMs differs significantly, and misapplication of these treatments can lead to exacerbation of existing infections or complete treatment failure. This PhD project will help end the misdiagnosis of TB, and improve treatment prescribing, by developing and validating a cutting-edge diagnostic test to differentiate NTMs and MTBC strains using our industrial partner VIDIIA’s rapid AI-assisted diagnostics. The test will focus on MTBC’s and clinically relevant NTMs, such as M. abscessus. Many NTMs are ubiquitous in the environment and their presence in hospital water systems can be associated with calamitous outbreaks. Therefore, this diagnostic test will be adapted to be of use in patient and environmental samples. Initially, cutting edge bioinformatics will be used to further develop the differentiative test. Environmental diagnostics will be tested at UKHSA using their “model” hospital ward, before testing on real-life samples in the UK and in Ghana. This project could help save lives by enabling accurate and rapid diagnosis in high-burden areas, breaking the cycle of treatment failure, AMR, and disease transmission. Students will gain valuable experience in bioinformatics, molecular diagnostics and translational science, while contributing to a project with real-world impact on global health.

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Alessandra Pinna, a.pinna@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Ines Ruedas-Torres, Ines.RuedasTorres@ukhsa.gov.uk

Project Summary

Tuberculous Meningitis (TBM) is the most severe and difficult to treat form of tuberculosis, arising from bacillary penetration into the brain subarachnoid space, which triggers an inflammatory cascade. Worldwide, around 164,000 individuals develop TBM annually, and 150-200 cases are reported in the UK. Mortality is high: up to 60% in HIV-co-infected adults and 20% of children will die; 30% and 20% will suffer long-term after-effects. Current TBM treatment is based on the treatment strategies for pulmonary tuberculosis (TB) with a combination of antibiotics including rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). Treatment of TBM has poor outcomes because suboptimal doses reach the cerebrospinal fluid due to poor blood-brain barrier (BBB) penetration. Incomplete patient adherence to complex and prolonged regimens can complicate the situation contributing to the growing problem of antimicrobial resistance (AMR). There is an urgent clinical need for alternative treatments that overcome these issues. 

Objectives:

1. engineer biodegradable mesoporous silica nanostar(MSNS) that can cross the BBB and deliver drugs to infection sites, initially focusing on TBM.
2. load MSNS (vehicle), with antibiotics (drugs), nanoceria (anti-inflammatory agent) and super-paramagnetic iron oxide NP (SPION; image contrast agent) and to add mannose (Man; microglia targeting) and transferrin (Tf; BBB targeting) moieties on MSNS surface. Each design feature will be tested in in vitro BBB model to optimise the MSNS system for in vivo validation.
3. determine the proteome dynamics modulated by the nanostar vehicles with various combinations of antibiotics and antioxidants by quantitative mass spectrometry.

This work serves as an extreme model for other difficult-to-treat forms of both pulmonary (fibrotic unresolving cavities into which drug penetration is poor) and extrapulmonary (lymph node, genitourinary, renal, abdominal, and pericardial). Moreover, the  nanostar-drug formulation is a platform technology that could be used to treat other brain disorders (e.g., brain cancer, Alzheimer's, Parkinson's, etc.)

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Jennifer Ritchie, j.ritchie@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Claire Jenkins, Claire.Jenkins@ukhsa.gov.uk

Case Partner: CEFAS: Home - Cefas (Centre for Environment, Fisheries and Aquaculture Science)

Project Summary

Vibrios are bacteria capable of causing disease in humans and crustaceans. As natural inhabitants of marine ecosystems, vibrios can accumulate in the digestive tracts of filter feeding shellfish destined for human consumption. With an increasing global demand for seafood and changes in the ecology of Vibrio populations because of climate change, data to support and inform national and international seafood policy are urgently required.

With access to a global repository of vibrios collected over several decades, you will work with world-leading Vibrio experts to investigate the factors that contribute to the emergence, biology and transmission of isolates negatively affecting human and crustacean health.

Project structure:

Objective 1: Perform an initial characterisation of Vibrio parahaemolyticus isolates in a global repository including those first reported from human outbreaks in the 1950s. Determine and compare isolate attributes including virulence and antimicrobial resistance profiles. Develop skills in bacteriology, molecular biology and the analysis and interpretation of genomic data.

Objective 2: Use a combination of bacterial genetics and infection assays to examine host-pathogen interactions of representative isolates leading to a deeper understanding of species pathogenicity. Uncover biomarkers pertinent for use in human and crustacean risk assessment. Develop skills in infection biology including pathology, fluorescence microscopy, and molecular genetics. 

This project is best suited to those with a strong interest and experience in Microbiology, Biological Sciences or closely related disciplines. Experience in the application of bioinformatic tools would be desirable. The individual will spend up to 15 months based at the Centre for Environment, Fisheries and Aquaculture Science (Weymouth) and work closely with individuals in the Gastro and Food Safety (One Health) Division of the UK Health Security Agency.

Theme(s): Detection, Prevention and Intervention

Lead partner: University of Surrey 
Supervisor: Diptesh Kanojia (DK); d.kanojia@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Victor J Del Rio Vilas (VDR), victor.delriovilas@ukhsa.gov.uk

Project Summary

The COVID-19 pandemic highlighted the inadequacies in pandemic preparedness. Ill-informed preparedness investment decisions, partly due to sub-optimal evaluation frameworks like the WHO’s Joint External Evaluations (JEE), have likely contributed to the poor response to the pandemic. These shortcomings are not restricted to COVID-19 but extend to other epidemic-prone and zoonotic diseases. 

The research will explore whether JEEs, that score capabilities on a 1-5 scale and produce associated narratives on strengths, challenges, capabilities, and recommendations accurately capture the underlying preparedness capabilities of countries, including specific capabilities against zoonoses. Using large language models (LLMs), Objective 1) this research will first describe patterns in the narratives across all JEEs conducted to date, to then test whether the narratives can predict the scores assigned to each capability. The project will Objective 2) develop approaches to improve the automated prediction of these scores with natural language explanations supported by a Retrieval Augmented Generation (RAG) framework. The methodology integrates predictive approaches using natural language embeddings for robustness, with explanation generation using LLMs in RAG for interpretability and analyses. The work will Objective 3) determine whether narratives align with the scores and identify any inconsistencies or biases in scoring across countries. Additional evidence such as the Performance of Veterinary Services will be tested for their efficient contributions to predictive accuracy. By triangulating findings with external data (e.g. zoonotic PROMED reports and WHO’s Disease Outbreak News), we will explore the derivation of weights to inform the required trade-offs among capabilities investments, currently not considered, to inform realistic National Action Plans for Health Security (NAPHS) and other financial commitments.

Use of LLMs provides a scalable and automated way to analyse preparedness frameworks, supporting evidence-based enhancements as this work ensures that computational methods provide the granularity required to inform NAPHS, strengthen health systems, and enhance global outbreak preparedness.

Theme(s): Detection, Prevention and Intervention; Infection and Cellular Biology

Lead partner: University of Surrey 
Supervisor: Qibo Zhang, Qibo.zhang@surrey.ac.uk

Joint partner: UKHSA 
Supervisor: Dr Julia Tree, Julia.Tree@ukhsa.gov.uk

Project Summary

Rationale 

Immunity against infection critically depend on T cell and antibody responses produced in the immune system. Development of immunomodulatory agents/drugs to enhance these immune responses 

is an important strategy for better efficacy of treatment such as antibody-based or anti-viral therapy. Testing of new drugs typically involves the use of animal models to generate pre-clinical data. There is a growing momentum to replace/reduce animal experimentation. The availability of complex in vitro models such as organoid cultures provides the opportunity to change the way animals are used. This PhD project aims to evaluate a laboratory system that mimics a human immune organ for testing new immunomodulatory agents.

Approaches

Dr Zhang’s lab developed an in vitro organoid system using cells from human immune tissues (surgical adenotonsillar tissue from children& adults) to study immune responses to vaccines. Based on this, the PhD project will further develop/evaluate a 3D immune organoid system for testing immunomodulatory agents to enhance T cell and antibody responses against virus infection including SARS-CoV-2 and HSV. 

The organoid system will be optimised and evaluated for detecting immune responses induced by the 

virus antigens, with/without immunomodulatory agents (e.g. TLR 2/4/9 ligands and IFNβ). State-of-the-art techniques including confocal fluorescence microscopy, flowcytometry and immunoassays etc will be used 

to evaluate immune responses (e.g. immune structure formation, phenotypic & functional T and B cell responses, and virus neutralisation). The effectiveness of immunomodulatory agents will be analysed by comparing responses induced by antigen stimulation with/without the agents.

The PhD student will be jointly supervised by multidisplinary teams at UoS (Dr Zhang and Prof Elliot) and UKHSA (Drs Tree and Horton), with expertise/experience in cellular immunology, anti-viral drug testing and viral infection biology. 

Impact

An in vitro immune organoid system with capacities for testing immunotherapeutic anti-viral agents and better predicting clinical outcomes in humans will speed up development of effective anti-viral drugs for humans.

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Infection and Cellular Biology

Lead partner: Pirbright Institute 
Supervisor: Steve Fiddaman, Steve.fiddaman@pirbright.ac.uk

Joint partner: University of Exeter 
Supervisor: Bram Kuijper, a.l.w.kuijper@exeter.ac.uk

Project Summary

Rationale

Marek’s Disease Virus (MDV) is a tumour-causing herpesvirus of chickens which is estimated to cost the poultry industry $1-2 billion per year. Over the last century, MDV underwent a considerable increase in virulence, thought to be driven by leaky vaccines and continued intensification of the poultry and egg industries. The current gold standard for assessing the pathotype (virulent, very virulent or very virulent +) was introduced in the late 1980s and relies on infecting chickens with a novel MDV strain and comparing pathology against prototype strains with different vaccination backgrounds. The method requires large number of chickens from a specific genotype, as well as access to specialist animal facilities and vaccine strains, making it an expensive, specialised process that has limited reproducibility across different laboratories and uses animals unnecessarily. Modernising and streamlining the process of pathotype identification, this project will establish novel methods to identify biomarkers of MDV virulence from whole-genome sequence data (Oxford Nanopore). 

Approaches

Working closely with the WOAH-accredited MDV Reference Lab at Pirbright and collaborators in other countries, you will generate a large dataset of MDV genomes using state-of-the-art long-read sequencing technologies. You will use computational methods to identify rapidly evolving regions and open reading frames in the MDV genome and identify putative points of recombination between strains (including vaccine strains). Targeted in vitro and animal experiments can then be used to functionally elucidate the contribution of polymorphisms to virulence. 

Impact

This work will establish a reference dataset of MDV genomes, identify putative virulence factors, and functionally validate these using laboratory methods, all of which will be of considerable value to the scientific community and industry. Moreover, the project will trailblaze the use of genomics to identify biomarkers of virulence rather than a reliance on live animals, consistent with a 3Rs framework for modern scientific research.

Theme(s): Understanding disease spread

Lead partner: Pirbright Institute 
Supervisor: Simon Gubbins, simon.gubbins@pirbright.ac.uk

Joint partner: University of Surrey 
Supervisor: Giovanni Lo Iacono, g.loiacono@surrey.ac.uk

Project Summary

Rift Valley fever virus (RVFV) is a zoonotic virus transmitted by mosquitoes that is endemic in Africa. RVFV causes abortions in livestock and potentially severe disease in humans and has been identified by the World Health Organization as a priority disease for research. Although cases have not been reported in Europe, mosquitoes and livestock in the region (including in Great Britain) are known to be susceptible to infection, raising the possibility of outbreaks should the virus be introduced.

This project will investigate the zoonotic spread of RVFV in a GB context following an incursion either via import of infected animals or wind-borne introduction of infected mosquitoes. It will consider three questions:

(i) What is the risk of onward spread in livestock?

(ii) What is the risk of spillover to humans and how does this risk vary amongst sectors of the population (e.g. farm workers, slaughterhouse workers or the general public)?

(iii) How might an incursion be detected (e.g. abortion surveillance, surveillance of livestock or workers at abattoirs)?

To address these questions mathematical models will be developed for the transmission of RVFV between livestock and mosquitoes together with spillover to humans, a key factor that is omitted in most existing transmission models. Uncertainty and sensitivity analyses will be used to identify and prioritise data gaps. Once the initial modelling has been completed, it will be used to guide project development. This could include generating additional data, extending the model to consider between-farm transmission and control measures or to consider how risks may alter under different climate change scenarios, depending on the background and interests of the student.

The project will inform outbreak preparedness in the event of an RVFV incursion, allow identification of critical data gaps and develop a framework that can be applied to other zoonotic arboviruses.

Theme(s): Understanding Disease Spread

Lead partner: Pirbright Institute 
Supervisor: Dr Marion England, marion.england@pirbright.ac.uk

Joint partner: University of Surrey 
Supervisor: Dr Martha Betson; m.betson@surrey.ac.uk

Project Summary

Urbanisation of the UK landscape creates novel habitats in which disease vectors may adapt and thrive or be unable to sustain viable populations. With a high human host density and low animal host density, urban areas may simultaneously enhance and reduce vector-borne disease risk. Oropouche virus (OROV) has recently been reported in Europe for the first time in infected travellers arriving from endemic areas and large outbreaks have occurred in central and South America in 2024. In South America, OROV is transmitted by the midge Culicoides paraensis but in northern Europe, very little research has centred on human biting of Culicoides midges. With the arrival of OROV to Europe, there is an urgent need to understand human biting by Culicoides to determine the potential for onwards transmission from imported cases. 

Co-incidentally, northern Europe is experiencing a large outbreak of bluetongue virus (BTV) that is affecting multiple countries including the UK. This outbreak has highlighted knowledge gaps around Culicoides dispersal and connectivity across the landscape. Urban areas may act as a barrier to infection but the extent to which Culicoides can exploit urban green spaces is unknown. 

This project explores human Culicoides-borne disease risk, and the role of urban areas in animal disease transmission by:

• Understanding Culicoides diversity, abundance and host feeding habits in a variety of urban environments
• Comparing Culicoides activity and seasonality in urban and rural areas
• Measuring changes in Culicoides diversity and abundance along an urban-rural gradient.

BTV transmission models currently do not incorporate landscape factors. Understanding Culicoides presence and temporal and spatial dynamics within urban areas can be built into BTV transmission models, increasing model accuracy used to inform policy decisions. It will also improve understanding of disease risk within urban environments from Culicoides-borne arboviruses with insights into UK vector capacity for OROV.

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Infection and Cellular Biology Understanding Disease Spread

Lead partner: Pirbright Institute 
Supervisor: Jane Edwards, jane.edwards@pirbright.ac.uk

Joint partners: University of Surrey  
Supervisor: Falko Steinbach, f.steinbach@surrey.ac.uk

Collaborative partner: APHA

Project Summary

Porcine reproductive and respiratory syndrome virus (PRRSV) causes one of the most important diseases affecting the global pig industry. Current vaccines provide some clinical benefit but fail to control the spread of PRRSV and rather drive antigenic diversification. Efforts to develop improved PRRS vaccines are hampered by an incomplete understanding of immunity. Protective neutralising antibodies are not observed until 4 weeks after infection and titres are lower than those elicited by other viral infections. This suggests that the germinal response required to generate an effective high affinity antibody response is impaired. We hypothesise that an imbalance between T follicular helper (Tfh) and T follicular regulatory (Tfr) cells dysregulates the positive selection and affinity maturation of antigen specific B cells and results in an ineffective neutralising antibody response. The overarching aim of this project is to better understand the immune response to PRRSV within infected secondary lymphoid tissue and how the virus may modulate this response to enable its persistence. This knowledge will inform the design of smarter vaccines.

The project will build upon ongoing research host-pathogen interaction research at all organisations involved. It will focus on the analysis of isolated Tfh, Tfr and B cells and a spatial transcriptomic analysis of longitudinally collected lymph nodes from infected pigs. It will apply ultrahigh-content imaging using the MACSima platform, which can label >100 biomarkers on the same tissue section, to understand changes in the cellular composition, relationships, and interactions within tissues. Time matched tissues from pigs vaccinated with a classical swine fever vaccine that induces a potent neutralising antibody response will be included as a comparator. The high-plex proteomic spatial data will be complemented by functional studies on isolated T and B cells and an assessment of the concomitant antibody responses.

Theme(s): Infection and Cellular Biology

Lead partner: Pirbright Institute 
Supervisor: Jonas Albarnaz,  jonas.albarnaz@pirbright.ac.uk

Joint partner: University of Surrey 
Supervisor: Sneha Pinto, s.pinto@surrey.ac.uk

Project Summary

In-depth characterisation of how different host species respond to viruses is crucial for understanding pathogenesis, disease outcome, and the design of effective interventions. Building on collaborative links between Pirbright and Surrey, our initial One Health-driven approach has been to assess the differential protein expression in three host cells (human, cow, pig) to investigate host responses to diverse RNA virus families, including coronaviruses, pneumoviruses, picornaviruses, flaviviruses, and orthomyxoviruses. Nine Pirbright-based research groups (Bailey, Tuthill, Keep, Sweeney, Maringer, Tchilian, Maier, Graham, and Dietrich) provided lysates from mid-exponential phase infections, with Surrey-based mass spectrometry (MS) specialists (Pinto) recently completing MS acquisition and quality control. Preliminary analysis integrating cross-virus species proteomic data reveals proteomic signatures shared between viruses as well as virus-specific proteomic changes. We are now perfectly placed for a PhD student to build on this unique resource, with parallel AI pathway analysis (Geifman), additional MS experiments (Pinto), and reductionist characterisation of enriched conserved pathways at the molecular detail (Albarnaz, Bailey). Building on the expertise of our supervisors and prior investment, the student will: 1. Onboard DNA virus-infected samples into MS analysis pipeline (lumpy skin disease virus, LSDV and cowpox virus, CPXV); (Pinto/Albarnaz) 2. Apply artificial intelligence (AI) to perform deep proteomics pathway analysis and identify shared proteomic signatures, irrespective of virus family and host species; (Pinto/Geifman) 3. Characterise enriched pathways at the molecular level using poxviruses (LSDV and CPXV) and pneumoviruses (bovine and human respiratory syncytial viruses, bRSV and hRSV) as experimental model systems. (Albarnaz/Bailey). Systematic collection and integration of parallel proteomic data from different viruses across different hosts will enable the AI-augmented dissection of complex cellular responses to viral infections and elucidate general biological principles that govern virus-host interactions and host spillover potential. Of note, the nine Pirbright groups involved initially are all supportive of this application.

Theme(s): Infection and Cellular Biology

Lead partner: Pirbright Institute 
Supervisor: Toby Tuthill, toby.tuthill@pirbright.ac.uk

Joint partner: University of Surrey 
Supervisor: Wooli Bae, w.bae@surrey.ac.uk

Project Summary

This interdisciplinary PhD project will use exciting approaches at the interface of virology, biophysics and synthetic biology to investigate a critical part of the virus life cycle: how viruses break through the barrier of the cell membrane to enter and infect cells. 

Foot-and-mouth disease virus (FMDV) is a high consequence animal virus which causes a global disease burden of $21 billion annually. During cell entry of FMDV, viral protein VP4 interacts with the cell membrane to induce permeability to allow virus entry. The mechanisms for permeability and for transfer of the viral RNA genome through the membrane are not understood. 

Phase one will use Giant Unilamellar Vesicles (GUVs) as biomimetic compartments to understand VP4-membrane interactions. We will perform membrane leakage assays to characterise permeability and pore formation by VP4. Synthetic biology and functional high throughput screens will be used to identify the effect of mutations on VP4 function. 

Phase two will use mutational scanning to reveal functional VP4 mutations which are tolerated in live virus. Selected mutant viruses will be characterised for altered ability to i) induce permeability in GUV and ii) to deliver viral genome into GUVs (containing RNA-sensitive fluorescent dyes). Bulk analysis will be complemented with single molecule fluorescence approaches on tethered GUV. 

This exciting combination of interdisciplinary approaches is novel but all the individual techniques are already established, therefore the project is likely to generate significant interesting data. This will advance our understanding of viral entry mechanisms and contribute to the development of novel antiviral strategies. 

Experienced supervisors will provide project guidance and mentorship. You will work in a team of scientists who will support you in a broad range of scientific techniques. Both partner institutions have excellent professional development programmes which will develop your transferable skills such as scientific writing, confident presenting and leadership.

Theme(s): Detection, Prevention and Intervention; Understanding Disease Spread

Lead partner: University of Sussex 
Supervisor: Fiona Mathews, f.mathews@sussex.ac.uk

Joint partner: APHA 
Supervisor: Daniel Horton, Dan.horton@apha.gov.uk

Project Summary

European Bat Lyssavirus I is a rabies virus found primarily in serotine bats. It is responsible for most bat rabies cases in continental Europe, and is highly pathogenic (fatal without vaccination) in humans. 

While historically absent from the UK, the virus was first identified in 2018 in Dorset. Whole genome sequencing points to a single introduction, probably from France (Golding et al. 2024).  More recently, cases have been confirmed in Somerset (c. 60km from the index case) and Devon (c. 110km from the index case, cases submitted by one of project supervisors). It is not yet known whether these recent cases share the same origin as those in Dorset. 

There is a pressing need to understand the future spread of rabies virus in serotine bats and to develop strategies, potentially including bat vaccination, to minimise the risk of disease transmission. Serotine bats usually roost in houses or churches, and all the cases identified were recovered by members of the public. The risk of direct viral transmission, as well as indirect transmission via domestic cats, is therefore very high. Climate change is also likely to exacerbate exposure risks as serotine bats are predicted to spread northwards (Filas et al. In prep); and cross-channel movements between France and Britain may also become more common.  
This PhD will provide vital evidence on the ecology and population dynamics of serotine bats; apply advanced radiotracking and geographical analyses; and conduct phylogenetic and epidemiological analysis, to identify key risks for human transmission and explore alternative management strategies. 

The project will benefit from an experienced and supportive supervisory team with expertise in ecology (Mathews), epidemiology (Nouvellet) and virology (Horton), and provide an exciting opportunity to work at the interface of academic environment and a government agency. 

Theme(s): Microbial Evolution and Drug Resistance; Understanding disease spread

Lead partner: University of Sussex 
Supervisor: William Hughes, william.hughes@sussex.ac.uk

Joint partner: APHA 
Supervisor: Nigel Semmence, nigel.semmence@apha.gov.uk

Collaborative partner: The Pirbright Institute

Project Summary

Honeybees are of tremendous economic importance, providing essential pollination services for many crops in addition to honey and other apicultural products. However, the productivity of apiculture, and the agriculture that relies upon it, is increasingly threatened by a diversity of pathogens, ectoparasite vectors and other stressors. There is growing recognition of the importance of the complex interactions between the host, pathogens and stressors, including those that may individually have only sublethal effects. Chronic Bee Paralysis Virus (CBPV) is a relatively neglected disease that is both an important problem for UK apiculture and an intriguing pathogen from a virology perspective. It is a single-strand, positive-sense RNA virus that has multiple modes of transmission, can replicate in multiple host species, causes multiple syndromes of symptoms, and often occurs at low prevalence but can cause rapid collapse of colonies and even whole apiaries. However, the virology and dynamics of CBPV are still poorly understood, which hinders the development of appropriate management strategies.

This exciting, cross-agency project will address this knowledge gap by investigating CBPV epidemiology and evolutionary dynamics at within-host, colony and population levels. Virus replication and mutation rates in different tissues and hosts will be examined to establish the significance of virus structure and how the virus persists within hosts. Laboratory experiments with controlled virus inoculations and qPCR will be used to examine the physiological basis for the different syndromes of symptoms and the dynamics of transmission between hosts. Field samples and syndromic surveillance will be incorporated into spatial and phylogenetic analyses to investigate virus patterns across the UK. The significance of interactions with other pathogens and stressors will be incorporated at all three levels. The results will both advance our fundamental understanding of host-virus dynamics and be of applied impact in informing the management of an important, neglected disease.

Theme(s): Detection, Prevention and Intervention; Understanding Disease Spread

Lead partner: University of Sussex 
Supervisor: Pierre Nouvellet, Pierre.nouvellet@sussex.ac.uk

Joint partner: APHA 
Supervisor: Ashley Banyard, Ashley.Banyard@apha.gov.uk

Project Summary

‘The COVID-19 pandemic exposed […] the need for sustained investment in pandemic influenza preparedness […] because, as we all know, an influenza pandemic is certain – the only question is when.’

Dr T.A. Ghebreyesus. WHO Director-General, High-Level Implementation Plan III 2024-2030

High pathogenicity avian influenza (HPAI) is a highly contagious and severe viral disease predominantly affecting birds but with a strong zoonotic risk. In Europe, HPAI is currently causing significant impacts on wild bird and poultry populations, with secondary risks towards public health.

Several countries have a thriving recreational and food supply gamebird industry, and populations significantly increase wild bird populations according to seasonal release. Such transient population explosions have been proposed to be linked to increased incidence of avian pathogens including avian influenza. We aim to define the impact of gamebird release on wild bird populations to better understand how these populations impact the disease and population ecology across the UK. Important components of this question include whether any changes to risk are important, and how they vary in space and time.

Methodologically, the project will involve both theoretical and data-driven approaches. Ecological data on gamebirds (using a combination digital sources and potential field work tracking birds post release) will be collected and combined with epidemiological data on bird die offs and links to avian influenza. Mathematical and statistical modelling will be used to predict the impact of gamebird releases on 1) disease dynamics, 2) predatory mammalian populations, and 3) potential mitigation strategies. The project aims to provide evidence on the eco-epidemiological impact of gamebirds and potential recommendations to mitigate pathogen risk.

The student will benefit from an experienced supervisory team with expertise in ecology and infectious disease modelling (Sussex/APHA), and veterinary epidemiology and virology (APHA) alongside providing an exciting opportunity to work at the academia:government interface.  

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Understanding Disease Spread

Lead partner: University of Sussex 
Supervisor: Leena Al-Hassan, l.al-hassan@bsms.ac.uk

Joint partner: UKHSA 
Supervisor: Paz Aranega Bou, Paz.AranegaBou@ukhsa.gov.uk

Collaborative partner: University of Exeter

Project Summary

Antibiotic resistance is a growing global health threat, where bacteria evolve and acquire mechanisms to resist antibiotics. Bacterial diversity is fuelled by horizontal gene transfer and the mobilisation of resistance and virulence mechanisms via plasmids and mobile genetic elements. This contributes significantly to the rapid spread of resistance and affects the pathogenicity, transmissibility, and persistence, which compounds the challenge of treating resistant infections across the One Health domain. Yet the exact transmission dynamics of plasmids are poorly understood, especially the impact on bacterial fitness across different ecological niches. 

The aim of this project is to study how plasmids persist and spread within and between different environmental niches, when subject to different selective pressures (i.e. the wider environment, exposure to antibiotics and disinfectants across the One Health sectors such hospitals, livestock and the food chain). Combining laboratory and computational approaches will identify what factors allow the success of certain plasmids across multiple bacterial species, and how they persist and spread in a) different bacterial hosts and b) different environments. Furthermore, measuring the speed of plasmid transfer among bacteria, as well as the fitness costs of harbouring and expressing these plasmids will reveal important insight into the resistance-virulence convergent plasmids observed more recently in hospital settings. 

This project will provide invaluable input in the field of infectious diseases by providing a comprehensive understanding of the role of plasmids in the acquisition and transfer of both antibiotic resistance and virulence, as well as demonstrate how plasmids contribute to bacterial adaptation, in response to different selective pressures (e.g. chemical disinfection) and environmental factors. This project will provide essential insights into the complex dynamics of bacterial pathogens, paving the way for improved interventions in infection prevention and control practices globally. 

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Understanding Disease Spread

Lead partner: University of Sussex 
Supervisor: Simon Waddell, s.waddell@bsms.ac.uk

Joint partner: UKHSA 
Supervisor: Simon Clark, Simon.Clark@ukhsa.gov.uk

Project Summary

Why do some bacteria cause opportunistic infections in people, and what can we do to prevent them? Non-tuberculous mycobacterial (NTM) infections are increasing in the UK and the world. These bacteria, found naturally in soil and water, cause opportunistic lung infections that may be acquired in hospitals. They cause disease most often in patients with chronic lung conditions such as COPD/bronchiectasis or in immunocompromised patients. The dispersal of NTM in water and aerosols is not well understood, and they are hard to kill with antibiotics. This project will characterise NTM in relevant infection models using a combination of cutting-edge molecular tools, including genomics and transcriptomics. The project will hopefully lead to novel strategies to prevent NTM infections, to eradicate biofilms, and to improve patient outcomes. The project builds on an existing partnership between the University of Sussex (Waddell) and the UK Health Security Agency (UKHSA) Porton Down (Moore and Clark), where we have identified NTM in water sources in hospitals. NTM likely colonise water systems by growing in biofilms, which may generate antimicrobial resistance (AMR) phenotypes. The experienced supervisory team has expertise in the molecular microbiology of Mtb and NTM (Waddell), Mtb and NTM models of infection (Clark), and the biology of waterborne bacterial infections (Moore).

The project will: (1) Define the Mycobacterium avium complex (MAC) phenotype (using transcriptomics and genomics) to life as a biofilm in hospital water systems, and in patient samples utilising a purpose-built Isolator to Measure Aerosol and Droplet GENeratioN (IMADGENN). (2) Characterise the impact of MAC lung and biofilm phenotypes on susceptibility to frontline antibiotics and disinfectants. (3) Map the adaptations necessary for MAC to establish an infection.

The project would suit a student who is interested in infection biology and in the application of molecular omics tools to drug discovery and infection control.

Theme(s): Detection, Prevention and Intervention, Infection and Cellular Biology

Lead partner: DSTL 
Supervisor: Robert Purcell, rpurcell@dstl.gov.uk

Joint partner: University of Surrey 
Supervisor: Kate English, Kate.english@surrey.ac.uk

Project Summary

Combat Casualty Care (CCC) research at Dstl investigates means of reducing mortality and morbidity in casualties of traumatic injury.  Pathophysiological responses to traumatic haemorrhage and resuscitation result in numerous sequelae in survivors, such as increased susceptibility to infection and the development of multiple organ dysfunction syndrome, increasing morbidity and mortality. 

The manifestation of persistent lymphopenia and immunosuppression following traumatic haemorrhage is well-recognised, and has been associated with wound infection, sepsis and multiple organ dysfunction syndrome.  The mechanisms are a subject of ongoing debate. 

This project will explore the potential mechanisms of lymphopenia, using a combination of in vitro models and archived samples obtained from terminally anaesthetised porcine models of traumatic haemorrhage and resuscitation.  Archived samples include tissues in RNA-later, formalin-fixed paraffin-embedded tissues, snap-frozen tissues, and blood-derived samples (e.g. serum, plasma). 

A multifaceted approach will provide the candidate with the opportunity to investigate the persistent lymphopenia from different angles, whilst learning numerous transferable laboratory and research skills (e.g. problem solving, working as part of a wider team, presenting results).  The candidate and their research will benefit from the collaboration between, and supervisory support from, multidisciplinary teams at Dstl and the University of Surrey.

There may be the opportunity to refine future sample archiving and analytical practices, based on the results from the work undertaken by the candidate.  This could include in ongoing CCC projects at the time the candidate is embedded in the team.  Refinement of approaches (sampling, archiving, analytical methods) contributes to improving the quantity and quality of data obtained from animal models.  Thus improving the ethical and scientific value of the research.

The outputs of the research will deepen understanding of the mechanisms of lymphopenia following trauma, and could provide insights into putative targets for therapeutic interventions, contribute towards the evidence base for different resuscitation protocols, and clinical biomarkers. 

Theme(s): Detection, Prevention and Intervention, Microbial Evolution and Drug Resistance, Understanding Disease Spread

Lead partner: DSTL 
Supervisor: David king, Dking1@dstl.gov.uk

Joint partner: University of Surrey 
Supervisor: Carlos Maluquer de Motes, c.maluquerdemotes@surrey.ac.uk

Project Summary

Currently, there are no rapid, accurate and cost-effective methods to predict the epidemic potential of viral populations, which hampers in-depth surveillance and vaccine development. Recent pandemics/global outbreaks caused by the SARS-CoV-2 and monkeypox (mpox) viruses have highlighted critical challenges, including deficiencies in early detection and surveillance. 

We hypothesize that a pangenome approach, combined with AI/machine learning, can predict epidemic potential. By integrating genomic features (such as genomic elements, protein domain structure, and mutation and recombination frequency) with host-virus interaction features (including viral load, transmission route, incubation period, and vaccination status), this project aims to identify and extract predictive genetic features that define viral strains of concern. Additionally, the project will employ spatial and dynamic phylogenetics and machine learning techniques to interpret repetitive patterns found in RNA/DNA sequence motifs and the high-dimensionality of RNA/DNA. These methods will be applied to sequences and epidemiological data obtained from the COVID-19 pandemic, representing a RNA virus model, and to current & future data from the current mpox international health emergencies, representing a DNA virus model. 

This project is at the forefront of the interface between virology, genomics and AI. You will collaborate with scientists from the Defence Science and Technology Laboratory (DSTL) and the University of Surrey to develop innovative machine learning approaches for detecting and predicting infectious disease epidemics. You will develop and apply computational methods to identify genetic signatures that indicate epidemic potential, leveraging large databases and exploring high dimensional machine learning methods, Bayesian statistics, phylogenetics, and/or spatially resolved models. The outcomes of this project will support health and security agencies in devising strategies to prevent and control infectious disease.

Theme(s): Infection and Cellular Biology

Lead partner: UKHSA 
Supervisor: Kathryn Ryan, Kathryn.Ryan@ukhsa.gov.uk

Joint partner: University of Exeter 
Supervisor: Gordon Brown, gordon.brown@exeter.ac.uk

Project Summary

We have recently discovered that MICL functions as a pattern recognition receptor (PRR) for neutrophil extracellular traps (NETs) (PMID: 39143217).  We have shown that NET recognition by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and further NET formation. Indeed, loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS/PAD4 pathway causing excessive inflammation during autoimmune and inflammatory diseases, including rheumatoid arthritis, Lupus and COVID-19 (PMID: 39143217). Notably, in these patient cohorts we discovered the presence of auto-antibodies against MICL that were inhibiting the key functions of this receptor, an observation we could recapitulate in animal models, at least for arthritis. 

This project is aimed at gaining mechanistic insights into the role of anti-MICL antibodies in SARS-CoV2 pathology, making use of the established Syrian Hamster model (PMID: 37014911) at the UK Health Security Agency, in which pulmonary NET formation is known to occur during SARS-CoV-2 infection (PMID: 33912167). We will establish the role of MICL during viral infection by determining the impact of modulating MICL function (using anti-hamster MICL antibodies we have generated, PAD4 inhibition, administration of DNase etc) on the severity of disease, viral burdens, NET formation (using markers such as cit-H3 and DNA/H1), cellular inflammation and tissue pathology (the former primarily through histology and immunofluorescence microscopy, given the absence of many anti-hamster specific reagents). Depending on progress, we will also study the impact of MICL during co-infection with Aspergillus fumigatus. In humans co-infection leads to serve disease outcomes in SARS-CoV2  infected patients (PMID: 34788127).  The outcomes of this project will feed directly into clinical cohort studies that are determining how the presence of anti-MICL antibodies impacts disease pathogenesis in patients.  

Theme(s): Detection, Prevention and Intervention

Lead Partner: UKHSA 
Supervisor: Matthew Wand, matthew.wand@ukhsa.gov.uk

Joint partner: University of Exeter 
Supervisor: Stephen Michell, s.l.michell@exeter.ac.uk

Project Summary

Burkholderia cepacia complex (BCC) is a species complex containing opportunistic human pathogens commonly associated with worsening outcomes in chronic infections such as cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease (COPD). People with CF are often on long term antibiotic therapy to suppress acute infectious episodes which can lead to the development of antimicrobial resistance. Alternatives to antibiotics are being investigated to either work in conjunction with or instead of antibiotics, for more successful treatment outcomes. One such alternative is the use of bacteriophages (phage) - viruses which infect bacteria. 

Phage are classified as virulent or temperate, with only the former currently suitable for therapeutic use. Virulent phage replicate exclusively by invading bacterial cells and hijacking host machinery to produce more phage before lysing the infected cell. Temperate phage can also integrate into the host genome, with potential for gene transduction and increased pathogen fitness. Few studies have investigated the efficacy of phage therapy in BCC, primarily due to a lack of clinically suitable phage. This project will isolate environmental phage against BCC and will characterise their host range, potential resistance mechanisms and synergy with antibiotics. To mitigate risks inherent in isolating natural phage against BCC, the project will also look at engineering biology approaches applied to modify temperate phage into an exclusively virulent genotype. Another engineering biology approach will be to repurpose exclusively lytic phage from closely related species such as Pseudomonas via tail fibre exchange with those derived from temperate BCC phage. 

Once a bank of phage which can infect BCC strains is established, the potential for phage treatment will be evaluated further using biofilm and infection models.  Both mono and polymicrobial infections will be studied in these models exploring the role of other problematic species associated with CF, such as Pseudomonas aeruginosa and Stenotrophomonas spp.   

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance

Lead partner: UKHSA 
Supervisor: Lucy J. Bock, lucy.bock@ukhsa.gov.uk

Joint partner: University of Exeter 
Supervisor: Stineke van Houte, C.van-Houte@exeter.ac.uk

Project Summary

Inflammatory bowel disease (IBD) is a complex, immune-mediated disorder that leads to chronic inflammation in the intestines and increased risk of developing colorectal cancer. Recent research highlights the role of an imbalanced gut microbiota in the onset and progression of IBD, with an overgrowth of pathogenic bacteria. One particular pathogen of interest is Escherichia coli, especially strains that produce colibactin – a mutagen that has been implicated both in the inflammation and colorectal cancer progression seen in IBD.

This PhD project aims to explore the potential of bacteriophages (viruses that infect bacteria) to control colibactin-producing E. coli in a synthetic gut community. The project will test wildtype and engineered phages, including phage cocktails, and investigate how the evolution of phage resistance in E. coli affects treatment success. Engineered non-replicative phages encoding CRISPR-Cas9 base editors will be used to disrupt colibactin biosynthesis without killing the host bacteria to reduce selection for anti-phage resistance and maintain ecological competition to prevent regrowth of resistant mutants. Modelling and experiments will be used to compare and contrast treatment outcomes between wildtype and engineered phages, and their consequences for gut microbiome dynamics (in collaboration with Prof. Brockhurst and Dr. Coyte at the University of Manchester).

As well as validating approaches for targeting colibactin-producing strains, the project will develop potential solutions that can be applied to pathogenic E.coli in different infection settings (e.g. Urinary Tract Infections), carrying other genetic constructs (carbapenemase-producing plasmids), as well as other pathogens (e.g. Klebsiella pneumoniae). Through this work, the student will gain expertise in phage biology, bacterial evolution, synthetic biology, and mathematical modeling, working within a collaborative environment involving the Westra and van Houte labs at the UoE, and the Sutton/Bock team at UKHSA and KCL. The project will leverage recent advances in phage engineering, biocontainment, and production from the BBSRC SafePhage project.

Theme(s): Infection and Cellular Biology

Lead partner: UKHSA 
Supervisor: Laura Hunter, laura.hunter@ukhsa.gov.uk

Joint partner: University of Surrey 
Supervisor: Tom Mendum, t.mendum@surrey.ac.uk

Case partner: Certara | Accelerating Medicines with Biosimulation and Tech-enabled Services

Project Summary

Mycobacterium tuberculosis is the leading single cause of death by an infectious disease, killing 1.3 million people in 2022. New antibiotics have recently been added to the multidrug panels that constitute the backbone of tuberculosis (TB) treatment. However, M. tuberculosis still presents a frustrating recalcitrance to drug therapy, with treatment regimens typically lasting from 4-6 months even for fully drug sensitive infections. In addition, the only available TB vaccine (BCG) provides only limited protection against infection. One of the main reasons that TB is difficult to target with drugs or immunological strategies is that the bacterium induces and establishes a protected niche in pulmonary granulomas, lesions comprising focussed clusters of immune cells. The granuloma is also the mechanism which drives TB transmission. Surprisingly, we don’t currently have a good understanding of the temporal and spatial dynamics of granuloma formation. 

In this project the student will characterise the cellular interactions during the development of the TB granuloma and will combine experimental laboratory-based analysis of immune cell populations and other immunological markers in TB granuloma tissues, with computational modelling of cellular interactions between the TB-bacillus and immune system. Mechanistic, dynamic models will be built in user-friendly software supporting modelling by biologists. The model will be calibrated with experimental data obtained by the student and used to facilitate understanding of complex underlying biology and generation of hypotheses for the next stage of experimental work. An understanding of the granuloma and the capability to computationally model the effects of drug/immune interventions will make a major contribution towards the development of novel TB control strategies.

The project will be based at UKHSA, but with aspects performed at the University of Surrey and with Certara, a company supporting drug development with modelling, thus providing a unique experience of research in university, government agency and industry environments.

Theme(s): Microbial Evolution and Drug Resistance, Understanding Disease Spread

Lead partner: UKHSA 
Supervisor: Steven Pullan, Steven.pullan@ukhsa.gov.uk

Joint partner: University of Sussex 
Supervisor: Adam Eyre-Walker, A.C.Eyre-Walker@sussex.ac.uk

Project Summary

Anthrax is a life-threatening zoonotic disease affecting animals and humans, caused by Bacillus anthracis. The life-cycle of B. anthracis includes environmental persistence as a highly durable spore, with a very limited evolutionary rate.

Disease in animals, particularly grazing herbivores, is often caused by ingestion of B. anthracis spores and human transmission typically follows contact with spore-contaminated animals or animal products. Examples of the latter transmission route include two fatal UK cases in 2006 and 2008, respectively, where patients had been in contact with spore-contaminated animal hides of West African origin. The UK samples could subsequently be phylogenetically linked to an anthrax outbreak in Sierra Leone, in 2022. 

These cases highlight the potential for attributing sources of anthrax outbreaks based on whole genome sequencing (WGS) and phylogenetic analysis. Phylogeny-based source attribution is highly dependent on the representativeness of the population used in the analysis.

In this project we aim to increase the accuracy of phylogeny-based anthrax source attribution, as well as further characterise the global population structure of B. anthracis in order to gain a better understanding of global distribution patterns. Specifically, a unique collection of >400 B. anthracis isolates, sampled over several decades and geographical locations by the UKHSA and predecessor organisations, both within and outside of the UK, will undergo WGS, (utilising combined long and short read data to achieve closed genomes) and be added to the global B. anthracis phylogeny, which is currently limited to approximately 2,500 genomes. 

Additionally, a bespoke Single Nucleotide Polymorphism (SNP) clustering pipeline will be developed in order to facilitate phylogenetic analysis of the UKHSA collection within the context of the publicly available B. anthracis genomes. The project will also investigate adaptive evolution in the core and accessory genomes of B. anthracis to gain a better understanding of how this important pathogen evolves.

Theme(s): Detection, Prevention and Intervention; Understanding Disease Spread

Lead partner: UKHSA 
Supervisor: Julie Robotham, Julie.robotham@ukhsa.gov.uk

Joint partner: University of Sussex 
Supervisor: Chris Hadjichrysanthou, c.hadjichrysanthou@sussex.ac.uk

Project Summary

Evaluations of the (cost-) effectiveness of interventions tackling antimicrobial resistant infections in hospitals have primarily focused on bacterial and viral infections, with fungal infections much neglected in the evidence base. 

However, with rates of fungaemia increasing by 22.3% between 2019 and 2023 in the UK, there is a need to strengthen the evidence base regarding optimal control options. 

Candidozyma auris (C. auris) is an emerging fungal pathogen worldwide and in 2022 was designated a critical priority by the World Health Organisation. In the UK, since 2023 there have been increased reports of colonisations, infections and outbreaks. 

Resistant to the first-line antifungal agent, C. auris can cause severe invasive infection with complicated treatment. While mortality associated with invasive C. auris is variably reported, in non-UK settings has been significant (up to 40-60%). It has high outbreak potential with these being disruptive, protracted and costly. 

Transmission models enable synthesis of the best available evidence leading to improved understanding of the epidemiolgy and a rational basis to determine optimal control strategies in terms of effectiveness and cost-effectiveness. 

Within this PhD, the student will develop mathematical and health economic models to explore the transmission dynamics of C. auris in English NHS hospitals and use these models to perform (cost-) effectiveness evaluations of alternative interventions leading to an improved evidence base for policy decisions. 

This will include four main components: 

1. Analysis of national/ local data to understand epidemiology e.g. the role of patient colonisation, environmental reservoirs and contamination to transmission, alongside pathogen/host factors
2. Estimating the health and cost burden of C auris in the English NHS
3. Model-based evaluation of the (cost-)effectiveness of alternative interventions e.g.:
4. Role of screening
5. Environmental cleaning
6. Diagnostics
7. A qualitative exploration of the barriers to infection prevention and control strategies and behavioural aspects of implementation. 

Theme(s): Detection, Prevention and Intervention

Lead partner: University of Exeter 
Supervisor: Camille Bonneaud, c.bonneaud@exeter.ac.uk

Joint partner: APHA 
Supervisor: Joe James, Joe.James@apha.gov.uk

Project Summary

The current panzooGc of H5N1 High Pathogenicity Avian Influenza Virus (HPAIV) has resulted in the death of over half a billion wild birds and poultry, with extensive spill-over events in wild and domesGc mammals, including infecGons in humans. CriGcal to this panzooGc is the high viral fitness across diverse avian species, although some species have remained overall unaffected despite being present in areas of high infecGon risk. Our understanding of species-specific variaGon in suscepGbility and infecGon dynamics is, however, limited to in vivo experimental infecGon studies, which are ethically and financially costly, and only provide limited insights into molecular and cellular level processes. The development of avian specific tools is therefore urgently required to clarify our understanding of the role that different species play in HPAIV epidemiology, virus evoluGon and zoonoGc risk. This studentship will develop and characterise cell lines from key bird species to determine the replicaGon kineGcs of avian influenza viruses, including host species-specific infecGvity and replicaGon, as well as the virological factors criGcal to infecGon outcome. The role of virological factors in shaping infecGon phenotypes will be invesGgated by loss-of-funcGon studies using reverse geneGcs (RG) techniques. We will combine experimental evoluGon on novel cell lines with viral sequence analyses to idenGfy the polymorphisms associated with adaptaGon to different host species. Furthermore, we will determine whether mammalian adaptaGons can be maintained in different species to improve predicGons of zoonoGc infecGon risks. Candidate mutaGons idenGfied will then be incorporated using RG and their phenotypic consequences assessed in both avian and mammalian systems. The project will fill a huge resource gap and provide valuable frontline tools required for in vitro studies. It will also allow invesGgaGons of fine-scale virus-host interacGons, with criGcal implicaGons for our ability to successfully predict future risks of HPAIV spread in birds and people.

Theme(s): Microbial Evolution and Drug Resistance

Lead partner: University of Exeter 
Supervisor: Dirk Sanders, d.sanders@exeter.ac.uk

Joint partner: APHA 
Supervisor: Rod Card, Roderick.Card@apha.gov.uk

Project Summary

Antimicrobial resistance (AMR) is causing a global health crisis. Plasmids are ubiquitous extrachromosomal elements that often carry AMR genes and are key vectors of AMR spread. Multi-drug resistant plasmids can spread throughout microbial communities and, more worryingly, between environmental, agricultural and clinical microbiomes, a threat acknowledged in the One Health concept. Two main environmental drivers may lead to the increased spread of AMR through plasmid transfer. First, even low concentrations of antibiotics in the environment make AMR carrying plasmids beneficial to their bacterial hosts and can therefore substantially drive plasmid prevalence and evolution. Second, biofilm formation has been shown to massively increase plasmid transfer (conjugation rates) between bacteria. Plastics are used at a large scale globally, for example in plastic packaging, the manufacture and laundry of textiles and the use of microplastics in wastewater treatment processes. This means plastic particles end up in the environment causing widespread pollution. Therefore, antibiotics and microplastics are key drivers in changing the way microbes interact. Sewage sludge is spread on agricultural land as a fertilizer and soil conditioner providing a pathway for microplastics, antibiotics and sewage linked AMR genes to enter the terrestrial environment. This project will investigate how antibiotic and microplastics interact in impacting the distribution and evolution of AMR plasmids that can spread resistance within and between microbiomes. This will be done by targeted experiments with synthetic microbial communities and investigations of complex microbiomes (e.g., sewage and seawater) using metagenomics and ecological network analysis combined with theoretical modelling. 

Theme(s): Understanding Disease Spread

Lead partner: University of Exeter 
Supervisor: Trevelyan McKinley, t.mckinley@exeter.ac.uk

Joint partner: APHA 
Supervisor: Dez Delahay, Dez.Delahay@apha.gov.uk

Project Summary

Identifying the drivers of heterogeneity in disease spread in mycobacterial infections is a major global priority, with regard to both human and animal health. Tuberculosis is thought to kill more humans globally than any other infectious disease, and bovine tuberculosis (bTB) is the most economically significant zoonotic disease of livestock and wildlife in the UK. In this project we will use an extraordinarily rich and globally unique dataset from a 50-year longitudinal study of bTB in European badgers at Woodchester Park, led by the Animal & Plant Heath Agency (APHA), to identify the origins of heterogeneity in the acquisition-of-infection, disease progression, and the triggering of onward transmission. The project builds on a long-standing close collaboration between Exeter and APHA.

Specifically, we will extend recent work on efficient Bayesian inference methodology for fitting mechanistic infectious disease models to individual-level data, to gain important insights into key drivers of infection heterogeneity, including the roles of (i) host senescence (given our evidence of senescence in relevant immune parameters and fitness components in this population), (ii) genetic differences among hosts (exploiting a genetic pedigree to test for heritable variation in key epidemiological parameters), (iii) how duration of infection affects mortality and diagnostic test performance, (iv) whether proxy measures of immune response impact transmission potential over time, and (v) exogenous causes of variation in disease spread.

While elucidating the key drivers of disease spread is critical for the design of effective interventions, attempts to do so in human populations are hampered by the concurrent use of biomedical interventions to manage active disease. Our project offers an unprecedented opportunity to advance understanding of the infection biology of a globally significant infectious disease, and develop statistical tools that could be applied to other infectious disease systems utilising individual-level data, such as bTB in livestock.

Theme(s): Detection, Prevention and Intervention, Microbial Evolution and Drug Resistance, Infection and Cellular Biology

Lead partner: University of Exeter 
Supervisor: Elizabeth Ballou, e.ballou@exeter.ac.uk

Joint partner: DSTL 
Supervisor: Sarah Harding, svharding@dstl.gov.uk

Project Summary

Combat-related invasive fungal infections are life-threatening complications of severe blast trauma. They are often caused by soil-dwelling Mucorales fungi with high-level resistance to most currently available antifungal drugs. Yet devastating mucormycosis is understudied and poorly understood. Mucorales infections can be polymicrobial: approximately 40% of clinical isolates host bacteria that can be either transiently associated or form obligate symbiotic relationships, termed holobionts. Importantly, our data demonstrate bacteria can mediate fungal virulence by 1) increasing fungal stress resistance and 2) secreting factors that block host responses. Clinical reports also suggest Mucorales can be reservoirs for bacteremia in vivo. Disrupting holobionts can reduce fungal fitness, so compounds that disrupt holobionts may offer an important opportunity for controlling and mitigating fungal infections, as well as reducing the severity and persistence of bacterial co-infections. To address this challenge, this project will identify conditions and inhibitors of Mucorales-bacterial interactions underpinning virulence and characterise their modes of action and impacts on pathogenic outcomes. 

The student will:

1. Perform high throughput screens to disrupt holobionts using panels of well-characterised chemical fragments, FDA approved and in-pipeline drugs.
2. Model the impact of established antimicrobials and novel compounds on bacterial-fungal interactions using ex vivo, in vitro, and microfluidics approaches.
3. Prioritize hits and characterise their modes of action using genetic and biochemical approaches.

Insights and outputs from this work will build on our growing understanding of Mucorales pathogenesis, the impact of endosymbiosis on infection outcomes, and the potential for antimicrobial interventions to improve patient outcomes.   

Theme(s): Microbial Evolution and Drug Resistance; Infection and Cellular Biology

Lead partner: University of Exeter 
Supervisor: Khushboo Borah Slater, k.borah-slater@exeter.ac.uk

Joint partner: DSTL 
Supervisor: Christopher Jenkins, cjenkins@dstl.gov.uk

Collaborative partner: University of Sussex

Project Summary

Nitrogen is a building block for living cells. Nitrogen metabolism is important for pathogens such as bacteria, virus, fungi and protozoa to survive, grow and cause infections in the host. We have identified serine nitrogen metabolism and enzyme SerC as a druggable target in Mycobacterium tuberculosis (Mtb), one of the world’s most successful pathogens (DOI: 10.1016/j.celrep.2019.11.037). Mtb is the causative agent of tuberculosis (TB) infection, killing over a million people every year. There are rising cases of drug resistance, and new treatments are urgently needed. Serine metabolic pathway is also present in other intracellular pathogens including but not limited to Coxiella Burnetti, that causes zoonotic Q-fever infection and is a potential biothreat. The fungal pathogen Candida albicans causes 150 million vaginal infections and 9995,000 deaths from systemic infection per year. Therefore, genes and pathways in nitrogen metabolism are attractive targets for developing new therapies against these pathogens. This project will improve our understanding of nitrogen metabolism across bacterial and fungal pathogens to provide new therapies for fighting antimicrobial resistance to improve human health and welfare. The project involves interdisciplinary approaches of metabolomics, metabolic modelling and fluxomics to identify the nitrogen-based nutrients (e.g. amino acids) that are used by the pathogens Mtb, C. burnetii and C. albicans inside the human host cells and their related metabolic pathways. Compounds will be screened against the target proteins, and in vitro molecular assays will be designed to test the hit compounds using protein biochemistry, crystallography, enzymology, and computational chemistry (e.g. molecular docking). The outcomes from this project will provide the best druggable candidates to be validated in animal models for pre-clinical assessments and to inform drug development pipeline. Overall, the project will improve our understanding of nitrogen metabolism in different human pathogens and deliver new broad-spectrum treatments for multiple diseases. 

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Infection and Cellular Biology; Understanding Disease Spread

Lead partner: University of Exeter 
Supervisor: Jonathan Phillips, JJ.Phillips@exeter.ac.uk

Joint partner: DSTL 
Supervisor: Peter Cook, P.C.Cook@exeter.ac.uk

Project Summary

Need

Our ability to plan for and respond to any emergent health challenge depends on our ability to detect and distinguish threats at the molecular level. To make effective clinical and community health decisions, we must accurately measure biomarkers of (i) fungal and microbial pathogens (ii) infection and (iii) drug levels in treated patients. Fungal targets and treatments are particularly underserved.

Currently, diagnostics for small molecules are:

• challenging to make
• require complex, expensive analysis
• unresponsive to emergent challenges

Vision

We will create a protein biosensor platform technology to detect target small molecules, ultimately in vivo³. Importantly, this will serve as a rapidly adaptable blueprint to detect new high value targets, for example to respond to:

• emergent threats
• new pathogenic serotypes
• individual patient’s personalised response.

Goals

Produce, test, optimise and validate protein biosensors targetting:

1. Patient fungal biomarker: Spore surface proteins to detect fungal sensitisation in the asthmatic population⁵.
2. Antimicrobial last line of defence: Excess kanamycin is highly toxic, causing blindness, therefore dose is critical – real-time pharmacokinetic monitoring will aid safe clinical use.

Opportunity

Until recently biosensors were limited to re-purposing naturally occurring components – e.g. we successfully developed a drug biosensor¹. Protein design AI tools (Nobel prize 2024: Chemistry) now enable de novo creation of proteins to bind potentially any target molecule. 

Activities 

Biosensor engineering: A bioluminescent (BRET) response, which is sensitive and robust to background noise, will be tightly coupled to target binding – overcoming prior limitations of tethering which resulted in inefficient, unstable biosensors. We will optimise physicochemical properties for efficiency and stability, enabling future extension to sense new targets

Impact

This robust framework will enable detection of a wide range of target molecules in future. We will work with clinical diagnostics experts to deliver a functional device to researchers and clinical decision-makers.

Theme(s): Detection, Prevention and Intervention, Understanding Disease Spread  
Lead partner: University of Exeter

Supervisor: Alex Hayward, alex.hayward@exeter.ac.uk

Joint partner: DSTL 
Supervisor: Tom Maishman, tmaishman@dstl.gov.uk

Collaborative partner: University of Surrey

Project Summary

This project will develop new approaches for: (i) detecting retroviral lineages, (ii) understanding the spread of retroviral disease, and, (iii) evaluating the potential for emergence and prevention of new high consequence retroviral threats. 

Retroviruses, such as HIV, can cause serious disease in humans, wild vertebrates, and livestock. These viruses have the unusual property of integrating into the host genome, occasionally resulting in an ‘endogenous retrovirus’ (ERV) if insertion occurs in the germline. Thus, ERVs can be considered ‘genomic fossils’ that provide a partial record of past infection, offering rare insights into host-virus interactions over time. 

Previous analyses have suggested that the diversity of exogenous retroviruses circulating among wildlife may be significantly underestimated. Consequently, systematic and quantitative tests for recent ERV activity and host-switching are essential for detecting and preventing future threats in humans, wildlife and agricultural lifestock. Additionally, the short genomes of retroviruses are potentially amenable to genome editing by malicious agents. This raises concerns over the creation of new superviruses for use in terror or warfare (e.g. engineered airbourne rapid-acting immunodeficiency viruses), by harnessing aerosol transmission routes employed by certain retroviruses (e.g. Jaagsiekte Sheep Retrovirus). 

The exponential rise in high-quality vertebrate genomes offers unprecedented opportunities to greatly increase understanding of the complex interactions between retroviruses and their hosts. This PhD will develop new computational approaches, including the use of artificial intelligence, to screen newly sequenced vertebrate genomes and undertake massive-scale retroviromic analyses, focussing on key aspects of retroviral biology, such as the molecular bases underlying host-switching and the structural evolution of key proteins involved in infectivity.

The PhD will involve a three-month placement with supervisors at The Defence Science and Technology Laboratory (Dstl), to review and develop retroviral detection protocols, and integrate these within existing pipelines and applications, towards enhancing security against neglected, but high consequence, future retroviral threats.

Theme(s): Infection and Cellular Biology 

Lead partner: University of Exeter 
Supervisor: Michael Schrader, m.schrader@exeter.ac.uk

Joint partner: The Pirbright Institute 
Supervisor: Nicolas Locker, Nicolas.locker@pirbright.ac.uk

Project Summary

Background

During infection, cellular organelles can be exploited by viruses to promote replication or by the host cell to generate immune responses. Peroxisomes are organelles involved in metabolic pathways regulating lipid synthesis and signalling cascades. Peroxisomes have been proposed to contribute to cellular defences against viruses, triggering antiviral immune signalling. In response, many viruses target peroxisomes to evade cellular antiviral response or remodel peroxisome lipid metabolism to favour replication (doi:10.1016/j.tcb.2024.11.006). FMDV is a highly contagious virus infecting a range of cloven-hoofed animals and a major threat to the livestock industry. FMDV circulates in cattle, pigs, buffaloes, sheep, and goats, with varying degrees of clinical outcomes and pathogenesis, and therefore has evolved to evade host responses in a species-manner. However, the molecular basis for these restrictions is unclear. 

Approach

To dissect how peroxisomes contribute to species-specific restriction of FMDV we will combine our expertise in peroxisome biology and virology. 

Objectives

To achieve this, we will:

1. Fingerprint how stimulation with viral mimics (dsRNA) alter peroxisome dynamics applying advanced imaging techniques, and biochemical analysis, in porcine PK15 cells, bovine MDBK cells, and buffalo BKC cells, the latter are of interest because they support replication despite clinical disease being limited in buffaloes. Human A549 cells will be included as FMDV has low infectivity for these cells, and humans are not susceptible to FMD. 

2. Establish how peroxisomes contribute to antiviral responses following stimulation with dsRNA, using cell lines with altered peroxisomes through knock out of their specific scaffolding proteins, and measuring the impact on antiviral signalling using reporter assays and qPCR. 

3. Characterise how FMDV differentially regulates peroxisome dynamics and function by applying advanced imaging and biochemical approaches. 

Achieving this will reveal novel antiviral functions of peroxisomes, their contribution to FMDV infection and in species-specific restriction of FMDV replication, highlighting novel therapeutic targets.

Theme(s): Detection, Prevention and Intervention; Understanding Disease Spread; Infection and Cellular Biology

Lead partner: University of Exeter 
Supervisor: Eduarda Santos, E.Santos@exeter.ac.uk

Joint partner: UKHSA 
Supervisor: Miriam Jacobs, Miriam.Jacobs@ukhsa.gov.uk

CASE partner: CEFAS Home - Cefas (Centre for Environment, Fisheries and Aquaculture Science)

Project Summary

Environmental chemical exposure can alter immune function in animals ranging from humans to aquatic animals, and from vertebrates to invertebrates, leading to compromised responses to infectious diseases, such as fungal infections. The number of environmental chemicals with known immunotoxic activity is extensive and includes metals, dioxins, pesticides and many chemicals that disrupt the immune system indirectly via disruption of endocrine pathways (Zerdan et al, 2021; https://doi.org/10.3390/ijms22158242). However, substantial gaps remain in the understanding of chemical hazards explicitly associated with immunotoxicity and resulting in adverse effects on wildlife, farmed animals and humans, in particular in the presence of pathogens. This is an overlooked, yet critical area to address in chemical hazards and risk assessment.

This PhD will explore how environmental chemicals disrupt the normal function of the immune system and modulate the response to model fungal pathogens of relevance to humans and aquatic animals, following an interdisciplinary approach.

The project will address the following aims:

1. Generate a comprehensive review of the environmental chemicals able to cause immunotoxicity based on the current literature
2. Perform a comparative genomics analysis of the immune pathways across vertebrates and invertebrate systems using the available genomic resources for aquatic animals.
3. Perform exposure experiments to suspected immunotoxic compounds in vertebrate (Arabian killifish; Aphanius dispar) and invertebrate (water flea; Daphnia pulex) models and assess the molecular and phenotypic effects on the immune system using transcriptomics and imaging techniques
4. Perform fungal infections (including Candida and common fungal pathogens of aquatic crustaceans) in the presence and absence of immunotoxic compounds to determine whether immune responses to fungal pathogens are affected by the chemical exposures.

This multidisciplinary approach will ultimately support predictive assessments of chemical hazards with the potential to affect both human and marine health and compromise their response to pathogens. 

Theme(s): Detection, Prevention and Intervention, Microbial Evolution and Drug Resistance

Lead partner: University of Exeter 
Supervisor: Elaine Bignell, e.bignell@exeter.ac.uk

Joint partner: UKHSA 
Joint partner supervisor: J. Mark Sutton, mark.sutton@ukhsa.gov.uk, 

Collaborative partner: King’s College London, Institute of Pharmaceutical Science.

Project Summary

Fungal infections now kill more people worldwide than malaria and similar numbers to tuberculosis. There are currently only three drug classes available as monotherapy, and the frequency of fungal antimicrobial resistance is increasing rapidly all over the globe. ERB-azoles are a new functional class of existing antifungal agents that retain the ability to inhibit the antifungal target Erg11, whilst simultaneously resisting export by highly conserved drug efflux pumps that operate in Candida species, including the newly-emerged multidrug resistant pathogen Candida auris, identified by the World Health Organisation as a critical priority for global research and develoment.  ERB- azoles work as inhibitors, and also block their own transport through efflux pumps, resulting in high intracellular concentrations of ERB-azoles within the fungal cell. Our in vitro data suggest that increased retention of ERB-azoles is sufficient to make azole-resistant Candida isolates susceptible to ERB-azoles, even in the presence of multiple ERG11 target mutations.

This project will aim to address the following questions:

1. How can computationally-aided drug design and CRISPR-mediated gene editing optimise ERB-azoles to specifically inhibit Mdr1 and Cdr1 in Candida auris ?

2. How does efflux pump inhibition affect biofilm formation, virulence, and drug resistance in C. auris?

3. What is the efficacy of ERB-azole compounds in complex biological systems, particularly during systemic infection of mammals?

4. What is the spectrum of activity of ERB-azoles against other fungal pathogens of man?

Beyond developing new ERB-azole antifungals, this research offers a basis for developing antifungal strategies based on moderating efflux liability that might prove clinically useful as novel mono- or combination antifungal options in multiple other fungal pathogens.

Theme(s): Microbial Evolution and Drug Resistance, Infection and Cellular Biology, Understanding Disease Spread

Lead partner: University of Exeter 
Supervisor: Neil Gow, n.gow@exter.ac.uk

Joint partner: UKHSA 
Joint partner supervisor: Andrew Borman, andrew.borman@ukhsa.gov.uk

Project Summary

Mucosal (thrush) co-infections of Candida albicans and Nakaseomyces glabratus (Candida glabrata) are common but we do not know the immunological or pathological consequences that drive disease outcome. The global burden of vaginal candidiasis is estimated to be 103–172 million per year (PMID: 30078662).   We have the combined expertise to establish how tissue invasion and immune responses differ in Candida co-infections and mono-infections. These two distantly related species have marked differences in key aspects of their capacity to cause disease and resist antifungal drug therapy. In particular we know that cell wall differences differentially modulate immune recognition and signalling and that zinc acquisition via the Pra1 zincophore system is critical for neutrophil recruitment associated with C. albicans, but not N. glabratus infections (PMID: 38055800).  This project will therefore characterise the immune and pathological outputs of mono compared to co-infection models. The student will use assays for cytokine production, immune cell recruitment, phagocytic killing, NET formation, vaginal epithelial cell viability, and drug susceptibility in relation to mono-infections or  coinfections with recent clinical isolates obtained from the UKHSA Mycology Reference Laboratory, Bristol. Comparisons will be made in paired mono- and mixed infections with C. albicans isogenic mutants lacking Pra1 and in mutants made in our laboratories (PMID: 38055800, PMID: 33364531, PMID: 3755987) in both C. albicans and N. glabratus lacking key immune reactive cell wall components (N-mannan, O-mannan, glucan and chitin) to determine the relative contribution of specific virulence attributes to the co-infection disease profile. Whole genome sequencing analysis will be used to further investigate co-infection isolate pairs where high levels of disease severity were noted.  The Bristol UKHSA also sees examples of invasive C. albicans and N. glabratus bloodstream co-infections. Hypotheses emerging form studies of vaginitis will inform experiments to examine the consequence of fungal co-infection for candidemia and invasive candidiasis.

Theme(s): Detection, Prevention and Intervention; Infection and Cellular Biology

Lead partner: University of Exeter 
Supervisor: Peter Cook, p.cook@exeter.ac.uk

Joint partner: UKHSA 
Supervisor:  Emma Kennedy, Emma.Kennedy@ukhsa.gov.uk

Project Summary:

Zika virus causes devasting foetal and early life pathology. Development of an effective maternal vaccination option could significantly prevent the prevalence of pathological infections. Maternal vaccination is a powerful intervention to reduce susceptibility to many life threatening infections from birth. We have discovered that optimal transfer of protective immunity from a vaccinated mother to their offspring is influenced by the maternal history of exposure to other pathogens. 

This project will establish how vaccination of mothers with irradiated Zika virus can protect mothers from infection and transfer early life protection to protection to offspring using mouse models. We will then test how maternal colonisation with Aspergillus fumigatus influences the efficacy of this immune transfer to offspring. Aspergillus infections are extremely common and leave a systemic footprint on the host immune system.

Ongoing and published work has already established maternal colonisation with, for example, helminths systemically changes mothers immunity and subsequently alters offspring ability to respond to related and unrelated infections. Moreover, we have also discovered that associated  changes that occur to a mothers immunity as result of pregnancy are critical for optimal transfer of protective immunity to offspring.

This project will first develop a maternal vaccination model that induces transfer of protective immunity to offspring in utero. It will then test how changes to mothers immunity as a result of colonisation with  Aspergillus fumigatus changes the magnitude of protection transferred to offspring. 

These findings will help guide how we optimise maternal vaccination in Zika endemic areas to protect infants from the devasting effects of this and related viral infections.

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Understanding Disease Spread

Lead partner: University of Exeter 
Supervisor: Rebecca Flemming, r.flemming@exeter.ac.uk

Joint partner: UKHSA 
Supervisor: Javier Salguero, Javier.salguero@ukhsa.gov.uk

Project Summary

Co-infections involving multiple pathogen species (viruses, bacteria, fungus, helminths etc) are increasingly recognised as a widespread epidemiological phenomenon representing serious and distinctive health problems in many areas. The particular significance of co-infections currently associated with HIV and COVID-19 serves to put the spotlight on an issue which has an important and shifting history. Co-infection has been suggested to explain features of past epidemics which do not really fit modern disease profiles, for example, such as the ‘Plague of Athens’, and there is speculation about the role of pathogen interactions in changing disease prevalences over time. 

This project will move beyond speculation to the first systematic investigation of co-infection as a historical phenomenon. This investigation will be by necessity interdisciplinary and experimental. It will bring together current scientific understandings of the workings and patterns co-infection with the widest array of evidence, approaches and techniques now available—from osteology to proteomics, close reading of ancient medical (and historical) texts to palaeogenetics—in an inclusive, one-health form (paying attention to the possibilities of fungal and helminth coinfections, for example, as much as viruses and bacteria, examining human and animal disease and their interactions). What seem to be the most appropriate methods and materials to use? Do they work? Require adaption? How are the different approaches best combined?

This project will have a threefold impact:

1. Generating knowledge and understanding of past patterns of co-infection and the eco-social circumstances in which they arose and shifted; thus providing indications of future patterns.       
2. Developing new methodologies for the investigation of past co-infections in a holistic way. It will also foster wider interdisciplinary collaborations across the sciences and humanities.
3. Contributing to training graduate students with the combination of interdisciplinary skills now necessary to pursue crucial research in the history of health and disease.

Theme(s): Detection, Prevention and Intervention; Infection and Cellular Biology

Lead partner: University of Exeter 
Supervisor: William Horsnell, w.horsnell@exeter.ac.uk

Joint partner: UKHSA 
Supervisor: Breeze Cavell, Breeze.Cavell@ukhsa.gov.uk

Collaborative partner: Moderna

Project Summary

Maternal vaccination is a powerful intervention against life threatening infections acquired in early life. We have discovered that optimal transfer of protective immunity from a vaccinated mother to their offspring is influenced by the maternal history of exposure to other pathogens (such as helminths and fungi). 

Infection from mother to offspring by Streptococcus agalactiae is the cause of devasting early life Group B Streptococcus (GBS) disease. Maternal antigenic history is likely to influence maternal and offspring GBS colonisation. In this project you will 1: establish how vaccination of mothers with vaccine candidates against GBS controls colonisation in mothers and transfers protection to offspring using mouse models. 2: You will test how maternal colonisation with the common pathobiont Candida albicans (fungal) influences maternal immunity to GBS.

Our ongoing and published work has established that maternal colonisation with helminths and fungal commensals systemically changes mothers immunity and the transfer of immunity to offspring. This can disrupt offspring ability to respond to related and unrelated maternal infections. We have also discovered that associated  changes that occur to a mothers immunity as result of pregnancy are critical for optimal transfer of protective immunity to offspring. The project will use our platforms established for studying vaginal immunity essential for understanding control of GBS in mothers.

These findings will discover and test how changes to a mothers immune system change immune mechanisms essential for a level of immune control of GBS that will protect mother and infants from this devasting disease.

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Understanding Disease Spread

Lead partner: University of Exeter 
Supervisor: Barbara Tschirren, b.tschirren@exeter.ac.uk

Joint partner: UKHSA 
Supervisor: Jolyon Medlock, Jolyon.Medlock@ukhsa.gov.uk

Project Summary

Antimicrobial resistance (AMR) is a key challenge of the 21st century, exaggerated by the extensive use of antibiotics in livestock [1]. Gamebirds are particularly likely to propagate AMR through ecosystems because, unlike other farmed animals, they are released into the wild. In the UK, approximately 47 million pheasants are set free annually for recreational shooting [2]. The rearing of these gamebirds often involves antibiotics [3], including those classified as ‘last-resort’ treatments [3]. Pheasants are important hosts for disease vectors, such as ticks, and the wide range of zoonotic pathogens they transmit. Tick-transmitted Borrelia burgdorferi sensu lato, the causative agent of human Lyme disease, is the most common vector-borne zoonotic pathogen in the northern hemisphere and a major public health concern [4]. Ongoing research in the group has shown that pheasants are highly competent hosts for Borrelia sp. and act as amplifiers for this zoonotic bacterium [5]. 

This project will use an integrative One Health approach to test how antimicrobial use in gamebirds affects AMR evolution and acquisition by zoonotic pathogens. Pheasants are released at clearly identifiable sites (‘release woods’), which can be matched to control woodlands where no pheasants are released. This quasi-experiment provides a unique and timely opportunity to quantify the impact of antimicrobial use in gamebird rearing on AMR occurrence and spread in space and time. We will use a combination of shotgun metagenomics and HT-qPCR technology to characterise the antibiotic resistome in released pheasants, as well as arthropod disease vectors and wildlife reservoir hosts across replicated gamebird-release and control woodlands. This project will provide insights into the impact of antimicrobial use in the gamebird industry on AMR evolution and acquisition by zoonotic pathogens of public health concern, and their spread in the wider landscape. 

Theme(s): Detection, Prevention and Intervention; Microbial Evolution and Drug Resistance; Infection and Cellular Biology; Understanding Disease Spread

Lead partner: APHA 
Supervisor: Guanghui Wu, Guanghui.wu@apha.gov.uk

Joint partner: University of Exeter  
Supervisor: Orly Razgour, O.Razgour@exeter.ac.uk

Project Summary

Bats, as indispensable components of ecosystems, play a vital role in protecting animals and plants (agriculture and forestry) by consuming insect pests, and often harbour zoonotic viruses. While European and Asian bats are better studied, research on the virome and the potential for pathogen spillover from UK bats remains limited.

At APHA, we annually receive > 1000 bat carcasses for lyssavirus testing and the majority of which are negative. Nevertheless, we detected the recent emergence of European bat lyssavirus (EBLV)-1 in Serotine bats and the continuous presence of EBLV-2 among Daubenton’s bats. Both viruses can cause rabies. Recently, targeted screening identified several coronaviruses in British bats suggesting the potential presence of unidentified pathogens. Approximately one-third of received bats reported animal contact (e.g., bite marks or capture by cats), and about 3% had bitten or scratched humans, highlighting the pathogen spillover risk. Because of geographical isolation, UK bats are likely to have a distinct virome. This hypothesis is supported by the fact that several European bat lyssaviruses have not been found in the same species of UK bats, even after 27 years of surveillance efforts.

To address the knowledge gap, we will use metagenomics to analyse UK bat virome across various sample types (including bat organs, gut content and guano). Once promising targets are selected, we will develop molecular (e.g., PCR), cell culture and serological assays (e.g., pseudotype viruses or peptide ELISA) to identify and characterise pathogens and to detect potential spillover events, using human and animal sera available at APHA. The student also can work with bat conservationists to obtain field samples for the work.

The study will generate valuable insights into diet (insect pest monitoring), insect viruses (arbovirus monitoring), potential pathogens for humans, animals (including bats) and plants, contributing to risk assessment, disease prevention, ecosystem health and methodology innovations.

Theme(s): Detection, Prevention and Intervention, Understanding Disease Spread

Lead partner: APHA 
Supervisor: Mirjam Schilling, mirjam.schilling@apha.gov.uk

Joint partner: University of Exeter 
Supervisor: Xav Harrison, x.harrison@exeter.ac.uk

Collaborative partner: University of Surrey

Project Summary

Wildlife are vital reservoirs of pathogens that can harm both animal and human populations. Approximately 70% of emerging infectious diseases in humans originate from animals, highlighting the need to understand pathogen dynamics across ecosystems. A critical first step in safeguarding public health is the early detection of pathogens, especially at the interface between wild and domesticated animals. There is an urgent need to fill knowledge gaps for understudied microbial groups like fungi and viruses in wild species, capable of acting as conduits of transmission between humans and the environment.

This project will investigate the role of foxes as sentinels of pathigen spread, building on existing work by the Genomics for Animal and Plant Disease Consortium (GAP-DCII) at APHA investigating the viromes of wildlife using a One Health approach. Foxes are widespread across rural and urban environments, and interact with diverse species that may act as pathogen reservoirs. Given their large territorial range, foxes provide a unique opportunity to study pathogen dynamics across different habitats.

The student will use metagenomics to characterize the complete microbiome of foxes (including viral, fungal and bacterial microbiotas) from both urban and rural areas, comparing these findings with those from small mammals and rodents. By expanding our understanding of the microbial diversity, the student will identify new or emerging pathogen threats.

This research will provide invaluable insights into the risks posed by wildlife to both domesticated animals and human health. It will also inform future surveillance strategies, helping to detect and respond to new pathogens before they spread. 

This project suit individuals with an interest in the ecology of disease and/or genetics. Experience in using bioinformatic tools would be desirable. The student will be based at APHA and work closely with individuals at the University of Exeter and University of Surrey. 

Theme(s): Detection, Prevention and Intervention; Understanding Disease Spread 

Lead partner: APHA 
Supervisor: Arran Folly, arran.folly@apha.gov.uk

Joint partner: University of Surrey 
Supervisor: Abel Ekiri, ab.ekiri@surrey.ac.uk

Collaborative partner: UKHSA

Project Summary

Usutu virus (USUV, genus: Orthoflavivirus), an emerging mosquito-borne virus in Europe, is now endemic in southern England, following its first incursion during 2020. The emergence of USUV has been linked to a 39% decline of blackbird (Turdus merula), in Greater London. Critically, USUV is closely related to West Nile virus (WNV, genus: Orthoflavivirus), having a similar enzootic cycle and climatic requirements, highlighting that the UK may be permissive for the establishment of other mosquito-borne viral zoonoses. Therefore, adequate surveillance is required to safeguard animal and public health and inform policy. 

Mosquito surveillance provides one mechanism to undertake high-throughput screening of vectors from areas deemed at risk of viral incursion. However, surveillance samples may be degraded, reducing the likelihood and quality of viral detection. Consequently, optimising virus detection in mosquitoes is critical for improving surveillance and our understanding of viral epidemiology, more broadly. This project aims to develop, trial and compare novel techniques, including the use of FTA cards, faecal traps, field-based LAMP assays, and optimised cold storage protocols, to address the challenges of maintaining viral integrity during surveillance operations. Sample integrity will be assessed through qPCR, sequencing, and virus isolation in BLS3 laboratories.

Alongside enhancing molecular viral detection, the candidate will engage citizen scientists to contribute to mosquito surveillance. Current procedures include the use of cold chain transportation, a costly requirement that is also logistically complicated. Engaging the public to collect data on mosquitoes, their ecology, and proxy data on virus circulation (identification of moribund animal hosts, for e.g.), would provide a powerful tool for expanding national mosquito surveillance while simultaneously educating the public on arboviruses and native mosquitoes. 

The findings of this project will inform evidence-based policy recommendations, improve surveillance capacity and enhance public and animal health responses to help mitigate the impact of emerging zoonotic viruses.

viromTheme(s): Detection, Prevention and Intervention; Understanding Disease Spread; Infection and Cellular Biology

Lead partner: APHA 
Supervisor: Marco Falchieri, Marco.Falchieri@apha.gov.uk

Joint partner: University of Sussex  
Supervisor: Ed Wright ew323@sussex.ac.uk

Collaborative partner: University of Surrey

Project Summary

The global impact of coronaviruses spans multiple species, often with species specific pathogens that have evolved towards infection of hosts. The infection of poultry flocks with infectious bronchitis virus (IBV), an endemic avian viral pathogen in the UK has a significant impact on UK PLC. IBV reduces meat yield in broilers, fecundity in breeders, and egg quality and production in layers and its estimated that IBV affects over 22.5 million birds per annum in the UK with the highest direct disease costs in poultry of over £24 million annually1 . Globally, an estimated 55 billion chickens are produced and a 10% reduction to industry through IBV infection is estimated to cost the global poultry industry £654 million each year2 . The SARS-CoV-2 pandemic demonstrated the rapid deployment of vaccines to protect human populations. Vaccines are also used to protect flocks against IBV but level of protection and antigenic relevance is poorly studies. Importantly, vaccine mismatch, vaccine escape and poor vaccination practices likely play a role in the changing antigenic diversity of circulating IBV strains in the UK. As with SARS-CoV-2, stakeholder confidence in vaccination approaches is significantly reduced where disease develops in the face of vaccination. This constitutes a significant problem as vaccination against IBV almost invariably occurs at both the hatchery and on farm and so a lack of confidence due poor protection from circulating strains impacts significantly upon willingness to vaccinate where benefits are not necessarily realised. This project aims to use multiple in vitro and in vivo approaches to evaluate immunological responses to different viral antigens. In doing so the sensitivity of serological detection methods will be compared to understand how vaccinal responses may be differentiated between.