Immune system dysregulation during COVID-19 illness remains an area of intense investigation. Excessive release of proinflammatory cytokines and multi-organ injury suggest aberrant control of the immune system. Given the established role of nicotinic acetylcholine receptors (nAChRs) in modulating inflammatory responses, we explored the possibility that the SARS-CoV-2 spike-protein may directly perturb this regulatory pathway. The spike protein contains a furin cleavage-site with sequence similarities to alpha-neurotoxins known to antagonize alpha7, alpha9, and alpha10 nAChR subtypes. To test whether this region of the spike protein can influence nAChR function, we synthesized short peptides corresponding to putative nAChR-interacting domains from several SARS-CoV-2 variants. Electrophysiological recordings from Xenopus laevis oocytes expressing human nAChRs revealed potent, virus-variant dependent inhibition of nAChR activity. In human monocytic THP-1 cells, these peptides reversed acetylcholine-mediated suppression of interleukin-1beta release. Our findings identify a potential molecular mechanism by which SARS-CoV-2 may directly suppress nAChR signaling on immune cells thereby amplifying inflammatory cytokine release. This work supports the broader concept that structural motifs present in the SARS-CoV-2 spike-protein can disrupt cholinergic anti-inflammatory pathways and elucidates a mechanism that may contribute to the pathophysiology and immune system dysregulation that can occur in severe COVID-19.
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