Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis

  1. Nilesh Kumar
  2. Bharat Mishra
  3. Adeel Mehmood
  4. Mohammad Athar
  5. M. Shahid Mukhtar

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Abstract

COVID-19 (Coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the pathophysiology of this deadly virus is complex and largely unknown, we employ a network biology-fueled approach and integrated multiomics data pertaining to lung epithelial cells-specific coexpression network and human interactome to generate C alu-3-specific human- S ARS-CoV-2 I nteractome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 target central nodes of host-viral network that participate in core functional pathways. Network centrality analyses discover 28 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host modifying responses and cytokine storm. Overall, our network centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into SARS-CoV-2 pathogenicity.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.09.033910: (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
    Human-SARS-CoV-2 interactome data acquisition: To build human interactome, we assembled a comprehensive protein-protein interactions (PPIs) comprising experimentally validated PPIs from STRING database32 and four additional proteomes-scale interactome studies i.e. Human Interactome I and II, BioPlex, QUBIC, and CoFrac (reviewed in33.
    STRING
    suggested: (STRING, RRID:SCR_005223)
    BioPlex
    suggested: (BioPlex, RRID:SCR_016144)
    Briefly, GEO2R utilizes limma R package.
    GEO2R
    suggested: (GEO2R, RRID:SCR_016569)
    limma
    suggested: (LIMMA, RRID:SCR_010943)
    Network topology analyses was performed using NetworkX66 (version 2.4) Python (version 3.7.6) package was used except weighted k-shell-decomposition for which we downloaded wk-shell-decomposition Cystoscope App (version 1.0).
    Python
    suggested: (IPython, RRID:SCR_001658)
    Cytoscape (Version 7.3.2) was used to visualize all the networks.
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)
    Gene Ontology Functional Enrichment Analysis: The functional enrichment analysis was done by Kyoto Encyclopedia of Genes and Genomes (KEGG)
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    , ingenuity pathway analysis (IPA), WikiPathways, GO biological process, ClueGO, and enricher for human phenotype ontology and rare diseases term with their statistically significant parameters67.
    ingenuity pathway analysis
    suggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)
    WikiPathways
    suggested: (WikiPathways, RRID:SCR_002134)
    ClueGO
    suggested: (ClueGO, RRID:SCR_005748)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 39. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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 10.1101/2020.04.09.033910 on bioRxiv