SARS-CoV-2 Spike Protein Induces an EAE-Like Model of Persistent Pain Through Neuroinflammation and Synaptic Remodeling

Introduction: The COVID-19 pandemic has highlighted the long-term neurological manifestations of Long COVID, including fatigue, myalgia and neuropathic pain. Autoimmune encephalitis (AE) has been proposed as a mechanism underlying these sequelae. Previous studies demonstrated structural homology between the SARS-CoV-2 Spike Protein (SP) and Myelin Oligodendrocyte Glycoprotein (MOG), an autoantigen used to induce Experimental Autoimmune Encephalomyelitis (EAE). We hypothesized that SP induces persistent pain through EAE-like mechanisms. Objectives: To establish and characterize an experimental model of Long COVID-associated pain. Methods: Wistar rats (protocol N°029/2024) were immunized with MOG_35-55, Total Spike (SP_Tot), Spike fragment (SP_249-278) or vehicle. Mechanical and thermal nociception were evaluated from 0–21 days post-immunization. Spinal cords were analyzed by metabolomics, Hematoxylin-Eosin staining, and immunohistochemistry for GFAP, IBA1, TNFα, MBP, FluoroMyelin™, CD4, CD8, SYP and PSD95. Anti-MOG and SP antibodies were measured, and splenic expression of IFNγ, IL6, TNFα, CTLA4 and PDCD1 was evaluated. Results: Immunized rats developed persistent hyperalgesia without classical EAE paralysis. Histology showed glial activation, inflammatory infiltrates, and increased TNFα in the dorsal horn. MBP staining was slightly reduced, whereas FluoroMyelin™ indicated preserved myelin. Metabolomics revealed altered excitatory synaptic pathways, supported by increased PSD95/SYP colocalization. Only SP_Tot induced antibodies, while anti-MOG levels remained unchanged. Splenic gene expression indicated a Th1/Th17-like profile. Conclusion: SP induces an EAE-like neuroinflammatory phenotype in which persistent pain is driven by neuroinflammation and synaptic remodeling rather than overt demyelination. This model provides a platform for investigating therapies for Long COVID-associated chronic pain. Acknowledgments: FAPERJ and CAPES.

Nat. Rev. Immunol. (2021) 21:529.