Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

  1. Lucy CK Bell
  2. Cem Meydan
  3. Jacob Kim
  4. Jonathan Foox
  5. Daniel Butler
  6. Christopher E. Mason
  7. Sagi D. Shapira
  8. Mahdad Noursadeghi
  9. Gabriele Pollara

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Abstract

Dysregulated IL-1β and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1β and IL-6 in COVID-19. We show that the expression of IL-1β or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1β and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood, but is not associated with severity of COVID-19 disease, length of stay or mortality. We propose that IL-1β and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activity in vivo , aiding quantification of the biological effects of immunomodulatory therapies in COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.22.202275: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data matrices were obtained from processed data series downloaded from the NCBI Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) or Array Express repository
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    (https://www.ebi.ac.uk/arrayexpress/).
    https://www.ebi.ac.uk/arrayexpress/
    suggested: (ArrayExpress, RRID:SCR_002964)
    Duplicate genes were removed after the first one identified using Microsoft Excel duplicate remover function.
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    Statistical analysis: All module score calculations were calculated in R v3.6.1 and RStudio v1.2.1335, using scripts generated and deposited in our previous publication (https://github.com/MJMurray1/MDIScoring) (Pollara et al., 2017).
    RStudio
    suggested: (RStudio, RRID:SCR_000432)
    Mann-Whitney tests, Spearman rank correlations and Kruskal-Wallis tests were calculated in GraphPad Prism v8.4.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has limitations. Despite drawing on four independent COVID-19 datasets, the sample sizes assessed in our study were still modest, especially for longitudinal samples, but this was limited by the data available. Assessments of the transcriptome from leucocytes and whole blood in COVID-19 may not be interchangeable and will need cross-validating, although both datasets demonstrated no association between IL-1β or IL-6 activity and severity of disease. Determining the sensitivity and specificity of the IL-1β and IL-6 response modules for their respective cognate cytokines was limited by the available datasets and the range of cytokine stimulation conditions performed in those experiments. Comparing the expression of these modules across a wider range of biologically paired cytokine stimulations will allow refinement of their accuracy. As the modules were generated from in vitro experiments, we sought to determine their applicability in vivo, assessing neutralisation of cytokine activity following immunomodulation with biologic agents in vivo. IL-1β activity in blood and in tissues was diminished days after canakinumab (fig 3) and anakinra (Pollara et al., 2019) administration respectively, but no equivalent datasets were available to assess the IL-6 response module in the same manner. Biobanked samples from ongoing tocilizumab clinical trials in COVID-19 and other diseases may provide an opportunity to validate IL-6 module performance in this way. In conclusion, our da...

    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

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  2. Version published to 10.1101/2020.07.22.202275 on bioRxiv