Dissecting the mechanism of Immunoglobulin-mediated alterations in ME/CFS using single-cells to organoids

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is a multi-factorial disorder with many potential triggers. The infectious origin hypothesis has gained importance after increasing numbers of SARS-CoV-2 infected patients started developing ME/CFS-like symptoms, which are now called long COVID. Autoimmunity is implicated as an important clinical feature of both ME/CFS and long COVID. Recent pre-prints from two independent labs show the development of ME/CFS-like clinical features in mice after passive transfer of immunoglobulins from patients. Our own work, funded by ME Research UK and Gordon Parish Charitable Trust, convincingly shows IgG from ME/CFS patients induce mitochondrial dysfunction in primary endothelial cells. However, one of the major bottlenecks of current methodologies is to assign a functional and molecular relevance of autoimmunity to the development and progression of the disease. The current proposal uses systems biology and a cross-disciplinary approach in single-cells to 3D tissue organoids to identify and characterize functional cell- and tissue-specific targets of immunoglobulins associated with ME/CFS that will help us develop different therapeutic intervention strategies. Therefore, the proposed study aims to –

1. apply IgG fractions isolated from ME/CFS patients and healthy controls to primary cells and 3D tissue organoids to understand short-term and long-term cellular responses to IgG at the RNA level. and
2. identify interacting cellular proteins of IgG derived from ME/CFS patients.