An Autoantigen Atlas From Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19

  1. Julia Y. Wang
  2. Wei Zhang
  3. Victor B. Roehrl
  4. Michael W. Roehrl
  5. Michael H. Roehrl

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Abstract

COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. We used DS-affinity proteomics to define the autoantigen-ome of lung fibroblasts and bioinformatics analyses to study the relationship between autoantigenic proteins and COVID-induced alterations. Using DS-affinity, we identified an autoantigen-ome of 408 proteins from human HFL1 cells, at least 231 of which are known autoAgs. Comparing with available COVID data, 352 proteins of the autoantigen-ome have thus far been found to be altered at protein or RNA levels in SARS-CoV-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a connection between COVID infection and autoimmunity. The vast number of COVID-altered proteins with high intrinsic propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients. The variety of autoAgs related to mRNA metabolism, translation, and vesicles suggests a need for long-term monitoring of autoimmunity in COVID. The COVID autoantigen atlas we are establishing provides a detailed molecular map for further investigation of autoimmune sequelae of the pandemic, such as “long COVID” syndrome.

An autoantigen-ome by dermatan sulfate affinity from human lung HFL1 cells may explain neurological and autoimmune manifestations of COVID-19.

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  1. Version published to 10.3389/fimmu.2022.831849
  2. ScreenIT

    SciScore for 10.1101/2021.01.24.427965: (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

    Experimental Models: Cell Lines
    SentencesResources
    HFL1 cell culture: The HFL1 cell line was obtained from the ATCC (Manassas, VA, USA) and cultured in Eagle’s Minimum Essential Medium supplemented with 10% fetal bovine serum (Thermo Fisher) and a penicillin-streptomycin-glutamine mixture (Thermo Fisher) at 37
    HFL1
    suggested: None
    Software and Algorithms
    SentencesResources
    Similarity searches were conducted between our data and the Coronascape database to identify DS-affinity proteins (or their corresponding genes) that are up- and/or down-regulated in the viral infection.
    Coronascape
    suggested: None
    Pathway and process enrichment analysis: Pathways and processes enriched in the putative autoantigenome were analyzed with Metascape (28).
    Metascape
    suggested: (Metascape, RRID:SCR_016620)
    The analysis was performed with various ontology sources, including KEGG Pathway, GO Biological Process, Reactome Gene Sets,
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    GO Biological
    suggested: None
    Protein-protein interaction network analysis: Protein-protein interactions among collections of DS-affinity proteins were analyzed by STRING (51), including both direct physical interaction and indirect functional associations.
    STRING
    suggested: (STRING, RRID:SCR_005223)
    Literature text mining: Literature searches in Pubmed were performed for every DS-affinity protein identified in this study.
    Pubmed
    suggested: (PubMed, RRID:SCR_004846)
    Search keywords included the protein name, its gene symbol, alternative names and symbols, and the MeSH keyword “autoantibodies”.
    MeSH
    suggested: (MeSH, RRID:SCR_004750)

    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.

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  3. Version published to 10.1101/2021.01.24.427965v1 on bioRxiv