Is there a viral or bacterial causative agents in chronic arthropathies

PROJECT OVERVIEW

Chikungunya (CHIK) is an exemplar viral infection that can drive painful polyarthritis in patients, likewise tick and companion animal driven infection by Borrelia species including burgdorferi, mayonii, hermsii and Bartonella henselae can drive chronic joint and lymph node inflammation. However, the link between these and other bacterial and virus infection and the molecular and cellular mechanisms driving immune mediated inflammatory arthropathies including Juvenile Idiopathic Arthritis, Rheumatoid Arthritis, and Psoriatic Arthritis and therapy induced inflammatory arthritis are unclear.  Likewise, the role of common infectious organisms including CMV and EBV in driving disease are unclear.  Using synovial tissue biopsies and patient blood samples combined with single cell biology including single cell RNA sequencing, spatial protein and transcriptome imaging and serum protein analysis this project will apply a systems-based approach to provide insights into viral and bacterial infections in disease mechanisms. These will include analysis of the T cell and B cell repertoire in infiltrating adaptive immune cells and the gene transcriptome of innate immune cells (monocytes, macrophage & neutrophils) and tissue microenvironment including fibroblasts and endothelium focusing on evidence for viral transcripts and bacterial products triggering processes in the synovium.  The long-term aim of this project is to provide a rational basis for prevention in higher-risk individuals through vaccination or treatments involving anti-viral/bacterial agents in combination with immune modulating therapeutics to provide longer term treatment for joint swelling and pain.  Mechanistic insight from infection driven inflammatory arthritis has the potential to make a step change in the treatment of immune mediated inflammatory joint pathologies triggered by unknown aetiologies.

This project will require a GMC licence and willingness to work in the Experimental Medicine Clinical Research Facility to take biopsies under ultrasound and work with patients.

KEYWORDS

Chronic inflammation, arthritis, viral infection, single cell biology, systems immunology

TRAINING OPPORTUNITIES

The applicant will work with biopsy teams to obtain synovial biopsies.  They will gain key experience in human tissue biology processing, spatial imaging and systems immunology including analysis of single cell biology and spatial transcriptomics.

KEY PUBLICATIONS

Bolton C, Mahony CB, Clay E, Nisa PR, Lomholt S, Hackland A, Chin PS, Smith CG, Alexiou V, Nguyen HD, Thyagarajan M, Shiekh Z, Davis P, Chippington S, Compeyrot-Lacassagne S, Davda S, Foley C, Turtsevich I, Ingledow B, Kupiec K, Kelly J, Hanlon MM, DiCarlo E, Jones LJ, Smith SL, Eyre S, Neag G, Kemble S, Madhu R, Palshikar MG, Korsunsky I, Gao C, Tran M, Dendrou C, Buckley CD, Coles MCC, Raza K,MAPJAG Study Group, Gravallese E, Filer A, Wei1 K, Eslam, Al-Abadi W, Rosser EC, Wedderburn LR Croft AP, Severity-associated molecular niches define the inflamed synovium in juvenile idiopathic 1 arthritis, in press, Science Translational Medicine, 2025 Jul 2;17(805):eadt6050. doi: 10.1126/scitranslmed.adt6050

Drennan GD, Provine NM, Harris SA, Otter A, Hollett J, Cooper C, De Maeyer RPH, Nassanga B, Ateere A, Pudjohartono MF, Peng Y, Chen JL, Jones J, Fadzillah NHM, Grifoni A, Sette A, Satti I, Murray SM, Cathy Rowe C, Mandal S, Hallis B, Klenerman P, Dong T, Richards D, James Fullerton J, McShane H, Coles MC, Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective cohort study and analysis of transcriptomic predictors of response. Lancet Microbe, in press 2025.

Thomas T, Friedrich M, Rich-Griffin C, Mathilde Pohin M, Devika Agarwa1 D, Pakpoor J, Lee C, Tandon R, Rendek A, Aschenbrenner D, Jainarayanan A, Voda A, Siu J, Sanches-Peres R, Nee E, Sathananthan D, Kotliar D, Peter Todd P, Kiourlappou M, Gartner L, Nicholas Ilott N, Issa F, Hester J, Jason Turner11, Nayar S, Mackerodt J, IBD Cohort Investigators, AMP RA investigators, Zhang F, Jonsson A, Brenner M, Raychaudhuri S, Kulicke R, Ramsdell D, Stransky N, Pagliarini R, Bielecki P, Spies N, Marsden B,Taylor S, Wagner A, Klenerman P, Walsh A, Coles M, Jostins-Dean L, Powrie FM, Filer A, Travis S, Uhlig HH, Dendrou C, Buckley CD, A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease, Nature Immunology, 2024.

Ng MTH, Borst R, Gacaferi H, Davidson S, Ackerman JE, Johnson PA, Machado CC, Reekie I, Attar M, Windell D, Kurowska-Stolarska M, MacDonald L, Alivernini S, Garvilles M, Jansen K, Bhalla A, Lee A, Charlesworth J, Chowdhury R, Klenerman P, Powell K, Hackstein CP; ICECAP Consortium; Furniss D, Rees J, Gilroy D, Coles M, Carr AJ, Sansom SN, Buckley CD, Dakin SG. A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nature Communications, 2024 Feb 19;15(1):1394. doi: 10.1038/s41467-024-45341-9. 

THEMES

Experimental Medicine, immunology, inflammation, systems biology

CONTACT INFORMATION OF ALL SUPERVISORS

mark.coles@kennedy.ox.ac.uk

christopher.buckley@kennedy.ox.ac.uk

calliope.dendrou@kennedy.ox.ac.uk

sarah.davidson@kennedy.ox.ac.uk