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

  1. Ulises Santiago
  2. Carlos J. Camacho

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Abstract

Sequence homology between neurotoxins and the site encompassing the furin cleavage site 680 SPRRAR 685 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.

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    SciScore for 10.1101/2022.02.18.481096: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The initial peptide structures were generated in Pymol.
    Pymol
    suggested: (PyMOL, RRID:SCR_000305)
    The molecular dynamics (MD) simulations were run with pmemd.cuda32–34 from AMBER18 using AMBER ff14SB force field35.
    AMBER
    suggested: (AMBER, RRID:SCR_016151)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The P681H mutation of the Alpha variant keeps a motif similar to α-conotoxin, with the important caveat that the aromatic ring of H681 forms a stacking interaction with R682. This motif no longer fits in the α9-nAChR binding pocket (Fig. 2B), preventing the interaction between the Alpha variant and the cholinergic inflammatory pathway via the α9 subunit. The same behavior is observed for Omicron, whereas Delta partially recovers the toxin binding motif, and, thus, some capacity to trigger this inflammatory pathway. As shown in Fig. 4, our findings accurately track the appearance of these different variants of concern and reported cases of Multisystem Inflammatory Syndrome in Children by the CDC. Our findings predict that Omicron has a significantly reduced risk to trigger MIS-C. Of note, the Alpha variant already showed a diminished risk of MIS-C. However, as noted in Fig. 4, the alpha variant always has some overlap with beta, gamma, iota and mu variants that are predicted to engage the cholinergic inflammatory pathway the same as wild-type SARS-CoV2. Collectively, our findings validate molecular modeling as an approach to probe the host/pathogen interactions. This advance allows us to test the functional impact of past and future mutations by in silico scanning physical interactions. Based on the insights borne out by the structural evolution at the furin cleavage site, we surmise that Omicron eliminated the risk of MIS-C. The ultimate question of whether the N679K/P681H mu...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2022.02.18.481096v1 on bioRxiv