Mechanisms of viral induced polyarthritis

PROJECT OVERVIEW

Chikungunya (CHIK) is a mosquito-borne alphavirus that has caused major outbreaks across Africa, Asia, and South America. While the acute infection is often self-limiting, a substantial proportion of patients develop persistent, painful polyarthritis that can significantly impair quality of life. The molecular and cellular mechanisms driving inflammation within the human joint synovium remain poorly understood, as do the similarities and differences between CHIK-induced arthritis and other inflammatory joint diseases, including Juvenile Idiopathic Arthritis, Rheumatoid Arthritis, Osteoarthritis, Psoriatic Arthritis, and therapy-induced inflammatory arthritis.

This project will combine synovial tissue biopsies and peripheral blood samples from patients with state-of-the-art single-cell and spatial multi-omics approaches to define the cellular and molecular pathways underlying CHIK-induced joint inflammation. Using single-cell RNA sequencing, spatial transcriptomics and proteomics, and serum protein profiling, we will apply a systems biology framework to characterise the immune and stromal cell networks that drive disease.

The study will investigate the T-cell and B-cell receptor repertoires of infiltrating adaptive immune cells alongside the transcriptional programmes of innate immune populations, including monocytes, macrophages, and neutrophils. These analyses will be integrated with detailed characterisation of the synovial tissue microenvironment, including fibroblasts, endothelial cells, and extracellular matrix-associated pathways, to identify the cellular interactions that sustain inflammation and tissue damage.

The long-term goal of this research is to establish a mechanistic framework for CHIK-induced polyarthritis that will inform the development of targeted therapies. By comparing CHIK arthritis with a spectrum of immune-mediated joint diseases, this work will also provide broader insights into the shared and disease-specific mechanisms that drive chronic inflammatory arthropathies in humans.

KEYWORDS

Inflammation, arthritis, infection, scRNAseq, systems-immunology

TRAINING OPPORTUNITIES

The applicant will gain key experience in human tissue biology processing and systems immunology including 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, Wei 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, Inflammation & Immunology, interacting systems, systems biology

CONTACT INFORMATION OF ALL SUPERVISORS

Mark Coles

Christopher Buckley

Calliope Dendrou

Sarah Davidson