Persistent serum protein signatures define an inflammatory subset of long COVID

  1. Aarthi Talla
  2. Suhas V. Vasaikar
  3. Gregory Lee Szeto
  4. Maria P. Lemos
  5. Julie L. Czartoski
  6. Hugh MacMillan
  7. Zoe Moodie
  8. Kristen W. Cohen
  9. Lamar B. Fleming
  10. Zachary Thomson
  11. Lauren Okada
  12. Lynne A. Becker
  13. Ernest M. Coffey
  14. Stephen C. De Rosa
  15. Evan W. Newell
  16. Peter J. Skene
  17. Xiaojun Li
  18. Thomas F. Bumol
  19. M. Juliana McElrath
  20. Troy R. Torgerson

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Abstract

Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months after acute SARS-CoV-2 infection. The etiologies are unknown but may include persistent inflammation, unresolved tissue damage, or delayed clearance of viral protein or RNA. Attempts to classify subsets of PASC by symptoms alone have been unsuccessful. To molecularly define PASC, we evaluated the serum proteome in longitudinal samples from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection and compared this to symptomatically recovered SARS-CoV-2 infected and uninfected individuals. We identified subsets of PASC with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), were the most differentially enriched pathways. These findings help to resolve the heterogeneity of PASC, identify patients with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance.

One Sentence Summary

Serum proteome profiling identifies subsets of long COVID patients with evidence of persistent inflammation including key immune signaling pathways that may be amenable to therapeutic intervention.

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  1. ScreenIT

    SciScore for 10.1101/2022.05.09.491196: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Informed consent was obtained from all participants at the Seattle Vaccine Trials Unit and the Fred Hutchinson Cancer Research Center Institutional Review Board approved the studies and procedures.
    IRB: Informed consent was obtained from all participants at the Seattle Vaccine Trials Unit and the Fred Hutchinson Cancer Research Center Institutional Review Board approved the studies and procedures.
    Sex as a biological variablenot detected.
    RandomizationFor plate setup, samples were randomized across plates to achieve a balanced distribution of age and gender.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Study data were collected and managed using REDCap electronic data capture tools hosted at Fred Hutchinson Cancer Research Center, including detailed information on symptoms during acute infection and longitudinal follow-up ranging from 33-379 days post symptom onset.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    The identified differential proteins from six symptom specific categories were merged together and their expression visualized in a heatmap using package ComplexHeatmap (v2.4).
    ComplexHeatmap
    suggested: (ComplexHeatmap, RRID:SCR_017270)
    A custom collection of genesets that included the Hallmark v7.2 genesets, KEGG v7.2 and Reactomev7.2 from the Molecular Signatures Database (MSigDB, v4.0) was used as the pathway database.
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    The “Type III interferon signaling” gene set was manually curated from the Interferome database 25.
    Interferome
    suggested: (Interferome, RRID:SCR_007743)
    Statistical analysis: All statistical analyses were performed using the corresponding functions in RStudio (version 4.1).
    RStudio
    suggested: (RStudio, RRID:SCR_000432)
    PASC patients from the inflammatory clusters 4 and 5 are represented here as inflammatory PASC (red), PASC patients from clusters 2 and 3 are represented here as non-inflammatory PASC (blue) while the recovered patients are represented in black.
    PASC
    suggested: (PASC , RRID:SCR_016642)

    Results from OddPub: Thank you for sharing your data.

    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.

    About SciScore

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  2. Version published to 10.1101/2022.05.09.491196v1 on bioRxiv