Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins

  1. Janelle Nunez-Castilla
  2. Vitalii Stebliankin
  3. Prabin Baral
  4. Christian A. Balbin
  5. Masrur Sobhan
  6. Trevor Cickovski
  7. Ananda Mohan Mondal
  8. Giri Narasimhan
  9. Prem Chapagain
  10. Kalai Mathee
  11. Jessica Siltberg-Liberles

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Abstract

Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. The coronavirus SARS-CoV-2 causes COVID-19, a disease curiously resulting in varied symptoms and outcomes, ranging from asymptomatic to fatal. Autoimmunity due to cross-reacting antibodies resulting from molecular mimicry between viral antigens and host proteins may provide an explanation. Thus, we computationally investigated molecular mimicry between SARS-CoV-2 Spike and known epitopes. We discovered molecular mimicry hotspots in Spike and highlight two examples with tentative high autoimmune potential and implications for understanding COVID-19 complications. We show that a TQLPP motif in Spike and thrombopoietin shares similar antibody binding properties. Antibodies cross-reacting with thrombopoietin may induce thrombocytopenia, a condition observed in COVID-19 patients. Another motif, ELDKY, is shared in multiple human proteins, such as PRKG1 involved in platelet activation and calcium regulation, and tropomyosin, which is linked to cardiac disease. Antibodies cross-reacting with PRKG1 and tropomyosin may cause known COVID-19 complications such as blood-clotting disorders and cardiac disease, respectively. Our findings illuminate COVID-19 pathogenesis and highlight the importance of considering autoimmune potential when developing therapeutic interventions to reduce adverse reactions.

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  1. Version published to 10.3390/v14071415
  2. Version published to 10.1101/2021.08.10.455737v3 on bioRxiv
  3. Version published to 10.1101/2021.08.10.455737v2 on bioRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.08.10.455737: (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

    Antibodies
    SentencesResources
    One of these hits corresponded to the human thrombopoietin (hTPO) protein (Epitope ID: 920946, UniProt ID: P40225.1, residues 131-135: TQLPP), where the structural representative for hTPO was found bound to the TN1 Fab antibody (PDB id: 1V7M, [11]).
    human thrombopoietin (hTPO) protein (Epitope ID: 920946
    suggested: None
    The contact area of the interface was calculated as (S1+S2-S12)/2, where S1 and S2 represent the solvent accessible surface areas of the antigen and antibody and S12 represents that for the complex (Fig.
    S12
    suggested: None
    Using the MaSIF protocol, we evaluated complexes of the TN1 antibody to bind Spike protein in the TQLPP region.
    TN1
    suggested: None
    Software and Algorithms
    SentencesResources
    To search EPI-SEQ, the amino acid sequence derived from PDB id 6XR8 (chain A) was used as the query in a local BLASTP search against EPI-SEQ using the BLOSUM62 matrix with both an E-value threshold and max target seqs value of 2,000,000, effectively turning off the E-value filter and removing the match limit, respectively.
    BLASTP
    suggested: (BLASTP, RRID:SCR_001010)
    In summary, TM-align performed the structural superposition step based on the BLAST alignment, calculated RMSD, and a TM-align score.
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)
    Geometrical alignments, as well as visualization, were performed with PyMOL version 2.4 (33) and Visual Molecular Dynamics (VMD 1.9.3, (34)).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Statistical analysis: Distributions were visualized as violin plots with ggpubr and ggplot2.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    Statistical analysis comparing the different distributions was performed using Mann-Whitney U with Scipy, followed by a simplified Bonferroni correction (alpha/n comparisons) when appropriate.
    Scipy
    suggested: (SciPy, RRID:SCR_008058)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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

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  5. Version published to 10.1101/2021.08.10.455737v1 on bioRxiv