A human coronavirus OC43‐derived polypeptide causes neuropathic pain

• Published in: EMBO reports 2022-06, Vol.23 (6), p.e54069-n/a
• Main Authors: Shubayev, Veronica I, Dolkas, Jennifer, Catroli, Glaucilene Ferreira, Chernov, Andrei V
• Format: Article
• Language: English
• Subjects: Affinity; Amino Acid Sequence; Amino acids; Animals; Conserved sequence; Cords; coronavirus; Coronavirus OC43, Human - physiology; Coronaviruses; COVID-19; EMBO23; EMBO27; Energy balance; Female; Homeostasis; Homology; Humans; Hypersensitivity; Mimicry; molecular mimicry; Myelin; Myelin basic protein; Na+/K+-exchanging ATPase; Na+/K+‐transporting ATPase; Nerves; Nervous system; Neuralgia; Neuraxis; Neurological complications; neuropathic pain; Pain; Pain perception; Peptides; Polypeptides; Proteins; Rats; Sciatic nerve; Signaling; Spinal Cord; Transcriptomes; Transportation; Viruses
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.202154069

Human coronaviruses have been recently implicated in neurological sequelae by insufficiently understood mechanisms. We here identify an amino acid sequence within the HCoV‐OC43 p65‐like protein homologous to the evolutionarily conserved motif of myelin basic protein (MBP). Because MBP‐derived peptide exposure in the sciatic nerve produces pronociceptive activity in female rodents, we examined whether a synthetic peptide derived from the homologous region of HCoV‐OC43 (OC43p) acts by molecular mimicry to promote neuropathic pain. OC43p, but not scrambled peptides, induces mechanical hypersensitivity in rats following intrasciatic injections. Transcriptome analyses of the corresponding spinal cords reveal upregulation of genes and signaling pathways with known nociception‐, immune‐, and cellular energy‐related activities. Affinity capture shows the association of OC43p with an Na + /K + ‐transporting ATPase, providing a potential direct target and mechanistic insight into virus‐induced effects on energy homeostasis and the sensory neuraxis. We propose that HCoV‐OC43 polypeptides released during infection dysregulate normal nervous system functions through molecular mimicry of MBP, leading to mechanical hypersensitivity. Our findings might provide a new paradigm for virus‐induced neuropathic pain. Synopsis A new paradigm for virus‐induced neuropathic pain could be based on molecular mimicry of the human coronavirus OC43‐encoded polypeptide (OC43p) with the pronociceptive fragment of myelin basic protein (MBP). Sciatic nerve exposure to OC43p produces sustained pain‐like behavior in rats. Transcriptional signatures of OC43p action feature pronociceptive, immune, and cellular energy signaling. Binding affinity of OC43p to Na + /K + ‐transporting ATPases reveals a potential direct‐action molecular mimicry mechanism in the nervous system. Graphical Abstract A new paradigm for virus‐induced neuropathic pain could be based on molecular mimicry of the human coronavirus OC43‐encoded polypeptide (OC43p) with the pro‐nociceptive fragment of myelin basic protein (MBP).