Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction

  1. Caroline Diorio
  2. Rawan Shraim
  3. Laura A. Vella
  4. Josephine R. Giles
  5. Amy E. Baxter
  6. Derek A. Oldridge
  7. Scott W. Canna
  8. Sarah E. Henrickson
  9. Kevin O. McNerney
  10. Frances Balamuth
  11. Chakkapong Burudpakdee
  12. Jessica Lee
  13. Tomas Leng
  14. Alvin Farrel
  15. Michele P. Lambert
  16. Kathleen E. Sullivan
  17. E. John Wherry
  18. David T. Teachey
  19. Hamid Bassiri
  20. Edward M. Behrens

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. Here we perform a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesize that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. We show that protein signatures demonstrate overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is an important marker of MIS-C that associates with TMA. We find that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity.

Article activity feed

  1. Version published to 10.1038/s41467-021-27544-6
  2. ScreenIT

    SciScore for 10.1101/2021.04.13.21255439: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study Approvals: This study was conducted in accordance with the Declaration of Helsinki and received approval from the Institutional Review Board (IRB) at CHOP.
    Consent: Verbal consent for this minimal risk study was obtained from patients or their legally authorized representative.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All assay validation data are available on the Olink website (www.olink.com). sC5b9 ELISA Assay: sC5b9 levels were determined using enzyme-linked immunosorbent assays (ELISA; Cat. #558315; BD Biosciences, San Jose CA, USA).
    Cat.
    suggested: None
    All analysis was performed in FlowJo (Treestar, version 10.6.2).
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    General statistical methods: All statistical analyses were performed in R (version 4.0.4) using RStudio (RStudio, PBC, Boston, MA).
    RStudio
    suggested: (RStudio, RRID:SCR_000432)
    The factoextra package (https://cran.r-project.org/web/packages/factoextra/index.html) was used to extract and visualize PCA elements.
    https://cran.r-project.org/web/packages/factoextra/index.html
    suggested: (factoextra, RRID:SCR_016692)
    We used the KEGG pathway database (https://www.genome.jp/kegg/pathway.html) which includes a manual collection of pathway maps examining a total of 777,729 molecular pathways, with 544 main pathways included.
    KEGG
    suggested: (KEGG, RRID:SCR_012773)

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.04.13.21255439v1 on medRxiv