Omicron and Alpha P680H block SARS-CoV2 spike protein from accessing cholinergic inflammatory pathway via α9-nAChR mitigating the risk of MIS-C

Sequence homology between neurotoxins and the site encompassing the furin cleavage site ₆₈₀SPRRAR₆₈₅ in the spike protein (S) of CoV2 suggested that this site could interact with nicotinic acetylcholine receptors (nAChRs). Molecular dynamics simulations confirm robust structural similarity between wild-type (WT) CoV2 and the binding motif of α-conotoxin to α9 nAChR, which is known to modulate IL-1β in immune cells. We show that the structural integrity of this binding motif is eliminated by Alpha P681H mutation, reemerged in Delta variant P681R, and disappeared again with Omicron N679H/P681H. Interactions between the toxin-mimic CoV2 motif and α9-nAChR are expected to trigger the release of pro-inflammatory cytokines an effect that is mollified by Alpha and Omicron. Clinical features of this interaction site are relevant because, contrary to most regions in the S protein, the furin binding site does not appear to trigger an immune response prior to cleavage, indicating that the cholinergic pathway should be activated in the respiratory tract and nasal mucosa where α9-nAChR co-localizes with the virus. The correlation of changes on this motif by the different variants closely matches the reported cases of Multisystem Inflammatory Syndrome in Children by the CDC, and predicts significant mitigation of MIS-C with the Omicron variant. Our findings strongly motivate further study of this cholinergic pathway as one source of the cytokine storm triggered by CoV2.