Passive transfer of IgG from patients with long-COVID neurological symptoms induces tactile allodynia in mice

Between 15% and 30% of SARS-CoV-2-infected people still experience neurological symptoms (memory impairment, attention deficits, pain) more than 4 months after the onset of COVID-19. This condition, long-neuro-COVID, is poorly understood and might be explained by a persisting autoimmune response against nervous-derived self-antigens. This study aims to determine whether IgG autoantibodies from long-COVID patients can bind to central and peripheral nervous system epitopes and reproduce neuropsychiatric symptoms upon transfer into mice. Long-COVID patients meeting the consensus WHO definition were included following a neuropsychological assessment. Age- and sex-matched asymptomatic individuals were used as controls. Total IgG was isolated using protein G purification and injected intraperitoneally into C57Bl6/J mice (8 mg/day) for four consecutive days. During the two weeks post-injections, depression and anxiety were assessed using the tail suspension test, the elevated-plus maze and the light/dark box. Spatial working memory was assessed using the Barnes maze and the Y-maze, and mechanical allodynia was assessed using Von Frey filaments. Mice injected with IgG from long-COVID patients showed no difference with the control group in terms of anxiety or depression behaviors, as well as no impairment of spatial memory. Mice receiving IgG from long-COVID patients displayed a significant decrease in paw withdrawal threshold in both hind paws, that was transient during the first week post-injections. These preliminary data show that IgGs from long-COVID patients can hyperactivate the nociceptive pathways and produce, at least in mice, pain-related symptomatology. Further analysis will aim at identifying the PNS or CNS targets.