Title: IMMUNE ANALYSIS OF LONG COVID TO INFORM RATIONAL CHOICES IN DIAGNOSTIC TESTING AND THERAPEUTICS
Funder: Department of Health and Social Care

Abstract: Long COVID sufferers report months of sequelae involving a varying flare and remission profile, including respiratory, cardiovascular, neurological/cognitive and gastrointestinal symptoms in unpredictable combinations. It remains unclear what the typical duration of long COVID symptoms will be. There is an urgent need to offer a comprehensive plan for clinical management, spanning diagnostic clarity centred on evidence-based biomarkers, and leading to rationally selected and trialled therapeutics. Both of these depend on considerable advances in current understanding of underlying mechanism. We previously proposed that Long COVID likely results from any or all of virus-induced tissue damage, reservoirs of persistent virus, dysregulation of immune subsets, and/or activation of autoimmunity. Preliminary evidence exists to support each of these. Characterisation of a causal role in disease pathophysiology would pave the way for definitive diagnostic assays and repurposing and trial of candidate therapeutics. This project will use molecular and cellular immunology analysis of samples from non-hospitalised Long COVID patients and controls to achieve these goals. The disease hypotheses share the property of implicating inflammation or immune perturbation. Once specific pathways have been better elucidated, translational immunology of the past few decades has supplied a well-stocked armamentarium of diverse biologics and other drugs that can be brought into action for trial and implementation. Our research agenda has been strongly patient-led and a PPI-centric approach will continue to inform investigations. Specific investigations to inform long Covid diagnostics and therapeutics are as follows: i) Multiparameter flow cytometric comparison of immune subsets in long Covid relative to healthy controls or people who made a full recovery from infection to define immune subset perturbations ii) Transcriptional comparison of immune subsets between these groups to define RNA biomarkers iii) Correlation of disease symptoms and MRI organ damage with specific patterns of antibody and/or T cell autoimmunity iv) Progress to pilot diagnostic tests

Lay abstract: Working with the Long COVID (LC) community, the applicants have argued the need for better understanding of the underlying mechanisms. With a more granular understanding of the precise mechanisms underpinning the diverse disease manifestations, one could both implement definitive diagnostic tests (which have been lacking) and identify those pathways implemented in the disease process and better understand the therapeutics likely to be most effective, an approach of 'less observation, more intervention'. Our studies encompass decades of work in autoimmunity, viral immunity, and the interface between the two in infections such as Chikungunya. Our starting point for this study is outreach to individuals who were not hospitalised but now have LC. Investigations start with the assumption that studies to define specific immune mechanisms in blood samples will supply diagnostic tests for healthcare application, as well as pinpointing the known therapeutics most likely to offer successful treatment. We hypothesised that LC may be the result of direct organ damage by the virus, reservoirs of persistent virus (for example in the gut), subsets of white blood cells in the immune system which are dysregulated following infection, or, as in Chikungunya, viral infection has triggered specific autoimmunity - that is, antibodies and/or T cells targeting self tissues to cause symptoms. We will invite study participants through adverts and through support groups, asking them to give a blood sample to look at three specific questions of immune dysregulation: 1. What is the evidence for disrupted white blood cell subsets in LC? 2. What is the evidence for RNA changes in T cells from people with LC, indicating an altered programming as suggested by the many who find that their allergy profile has changed 3. What is the evidence for specific autoimmunity correlated with LC? Deliverable: evidence-based diagnostic tests at the cellular, RNA and autoantibody level

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION