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

Abstract

Myalgic 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.