Defining the biology and chromatin architecture of Epstein–Barr virus infected B cells in early multiple sclerosis

About the Project

Title: Defining the biology and chromatin architecture of Epstein–Barr virus infected B cells in early multiple sclerosis

Synopsis: Epstein–Barr virus (EBV) is implicated as a causal driver of multiple sclerosis (MS), yet the biology of EBV-infected B cells in MS remains poorly defined. This project will characterise the phenotype, viral activity, and nuclear organisation of EBV-infected B cells in MS and during B-cell reconstitution after depletion therapy.

Details: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and a leading cause of neurological disability in young adults. A convergence of epidemiological, immunological and genetic evidence strongly implicates Epstein–Barr virus (EBV) as a causal factor in MS. Virtually all individuals with MS are EBV-seropositive, infection precedes disease onset by many years, and host genetic risk factors converge on pathways involved in antiviral immunity. However, despite this compelling evidence, the cellular mechanisms linking EBV infection to chronic neuroinflammation remain poorly understood.

EBV establishes lifelong latent infection in B lymphocytes, where the viral genome persists as an episome within the host cell nucleus. Our recent work in the FutureMS cohort has demonstrated that the abundance of EBV transcripts within circulating B cells varies between people with MS and healthy controls. Transcripts within cases, also predicts clinical and radiological measures of early neuroinflammatory disease activity. These findings suggest that EBV-infected B cells represent an active viral reservoir contributing to disease biology. However, we lack a detailed understanding of how EBV persists within B cells in MS, how these infected cells differ from those in healthy individuals, and how the viral reservoir responds to effective therapies, such as B-cell depletion.

This project will generate a comprehensive molecular and cellular description of EBV-infected B cells in early MS. The work will combine clinical cohort studies, viral immunology, and chromatin biology in an interdisciplinary collaboration between the Hunt and Gilbert laboratories.

The first objective is to define the cellular niche of EBV-infected B cells in MS. Using longitudinal samples from MS patients recruited through the FutureMS and PrecisionMS cohorts (led by PK and DH, respectively), the student will identify infected B cells using multiparameter flow cytometry combined with PrimeFlow RNA-FISH detection of EBV-encoded small RNAs (EBERs). These approaches will allow precise quantification of infected cells and characterisation of their B-cell subset identity and activation state.

The second objective is to characterise host and viral transcriptional programmes within infected cells. Bulk and single-cell RNA sequencing will be used to define viral gene expression patterns and host transcriptional responses associated with EBV persistence. Viral copy number and genomic sequence diversity will also be examined to determine whether viral strain variation or replication dynamics influence disease activity.

The third objective is to investigate how EBV episomes interact with host chromatin and nuclear architecture. Building on the expertise of the Gilbert laboratory in genome organisation, the student will use imaging approaches including immunofluorescence and expansion microscopy alongside chromatin profiling techniques such as CUT&Tag, ChIP-seq and ATAC-seq to determine how viral genomes are positioned within the nucleus and how they influence host transcriptional regulation.

A unique feature of the project is its longitudinal dimension. PrecisionMS provides repeated sampling of individuals receiving B-cell depletion therapies such as anti-CD20 monoclonal antibodies. The student will therefore examine how the EBV reservoir changes following depletion and during B-cell reconstitution, providing a rare opportunity to study the dynamics of EBV persistence during therapeutic intervention.

Potential impact: Understanding how EBV persists within B cells in MS may reveal new therapeutic strategies targeting the viral reservoir or its interaction with host chromatin. These insights could inform antiviral or immune-targeted interventions designed to modify disease progression.

Training: The student will be primarily based within the Gilbert laboratory at the MRC Human Genetics Unit, a leading centre for molecular genetics, genome biology and chromatin research. The lab provides a highly interdisciplinary environment combining molecular biology, genomics and imaging approaches to understand genome regulation and nuclear architecture. Within this setting the student will gain advanced training in modern genomic and cellular techniques used to study virus–host interactions.

The project will provide hands-on training in molecular and cellular methods including flow cytometry, RNA-based detection approaches such as PrimeFlow RNA-FISH, bulk and single-cell RNA sequencing, and chromatin profiling techniques such as CUT&Tag, ChIP-seq and ATAC-seq. The student will also gain experience in advanced microscopy approaches, including immunofluorescence and expansion microscopy, enabling investigation of viral genome organisation within the host cell nucleus.

Collaboration with the Hunt laboratory at the Centre for Clinical Brain Sciences will provide access to well-characterised clinical cohorts including FutureMS and PrecisionMS. Through this collaboration the student will develop an understanding of translational neuroimmunology, clinical cohort design and biomarker discovery in autoimmune disease. This integration of molecular biology with clinical research will allow the student to place mechanistic laboratory findings within a broader disease context.

The student will benefit from the extensive training programmes offered through the MRC Human Genetics Unit and the University of Edinburgh, including courses in genomics, bioinformatics, statistics and responsible research practice. Participation in lab meetings, interdisciplinary seminars and collaborative projects will support the development of analytical, technical and scientific communication skills.

Recruitment: This project would suit a student with a strong background in molecular biology, genetics, genomics or cell biology. Applicants should hold a good undergraduate degree (or equivalent) in genetics, molecular biology, biochemistry, biomedical sciences or a related discipline. Prior laboratory experience in molecular biology techniques (e.g. nucleic acid analysis, sequencing-based methods, microscopy or cell-based assays) would be advantageous but is not required. An interest in genome biology, chromatin regulation or virus–host interactions would be particularly valuable. The project integrates molecular and genomic approaches with clinical cohort research, and therefore applicants should be motivated to work across disciplinary boundaries. Basic computational skills or an interest in developing bioinformatics and data analysis skills (e.g. R, Python or genomic data analysis) would be beneficial.

Apply: All applications must be submitted through the Future Medicine PhD fellowships website.

Funding Notes

Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship. All University fees will be covered.

The fellowships are open to students who are eligible for home fees at Edinburgh - i.e. you must be a UK national, or have settled status, and have. been "ordinarily resident" in the UK for the three years immediately before the start of the fellowship. Other international applicants are not eligible for these fellowships.