Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID

• DOI: 10.1101/2023.06.23.23291827
• Publication Date: 2023-06-29T20:30:54Z
• Authors: Zheng Liu; Claudia Hollmann; Sharada Kalanidhi; Arnhild Grothey; Sam Keating; Irene Mena-Palomo; Stephanie Lamer; Andreas Schlosser; Agnes Kaiping; Carsten Scheller; Franzeska Sotzny; Anna Horn; Carolin Nürnberger; Vladimir Cejka; Boshra Afshar; Thomas Bahmer; Stefan Schreiber; Jörg Janne Vehres...; Olga Miljukov; Christian Schäfer; Luzie Kretzler; Thomas Keil; Jens-Peter Reese; Felizitas A Eichner; Lena Schmidbauer; Peter U Heuschmann; Stefan Störk; Caroline Morbach; Gabriela Riemekasten; Niklas Beyersdorf; Carmen Scheibenbogen; Robert K Naviaux; Marshall Williams; Maria E Ariza; Bhupesh K Prusty
• Keywords: Article; 3. Good health

SummaryMyalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions. Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS. Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.