CytokineLink: a cytokine communication map to analyse immune responses in inflammatory and infectious diseases

  1. Marton Olbei
  2. John P. Thomas
  3. Isabelle Hautefort
  4. Agatha Treveil
  5. Balazs Bohar
  6. Matthew Madgwick
  7. Lejla Gul
  8. Luca Csabai
  9. Dezso Modos
  10. Tamas Korcsmaros

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Abstract

Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine - cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from literature, and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated literature information on cell - cytokine interactions from two systems immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell-cell communication network connected by cytokines; and a cytokine-cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify inactive cell types and cytokine interactions that may be important following SARS-CoV-2 infection when comparing the cytokine response with other viruses capable of initiating a cytokine storm. Such findings have potential to inform the development of novel, cytokine-targeted therapeutic strategies. CytokineLink is freely available for the scientific community through the NDEx platform and the project github repository ( https://github.com/korcsmarosgroup/CytokineLink ).

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    SciScore for 10.1101/2021.08.10.455874: (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

    Software and Algorithms
    SentencesResources
    To achieve a broad coverage of cytokines, all cytokines listed in the ImmuneXpresso and ImmunoGlobe systems immunology databases were selected.
    ImmuneXpresso
    suggested: (immuneXpresso, RRID:SCR_017578)
    The metanetworks were created by generating all shortest paths of length five in the base network, with the get_simple_paths() function of the NetworkX (version: 2.5) python library (python version: 3.8.6).
    python
    suggested: (IPython, RRID:SCR_001658)
    The curated cell - cytokine and cytokine - cell interaction annotations from immuneXpresso and ImmunoGlobe were included in CytokineLink, assigning literature enrichment to the cell - cytokine associations to the underlying edges in the general network the metaedges were created from.
    CytokineLink
    suggested: None
    Expression data was downloaded from GEO and analysed using GEO2R.
    GEO2R
    suggested: (GEO2R, RRID:SCR_016569)

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    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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  2. Version published to 10.1101/2021.08.10.455874v1 on bioRxiv