Interplay of host regulatory network on SARS-CoV-2 binding and replication machinery

  1. Shiek SSJ Ahmed
  2. Prabu Paramasivam
  3. Kamal Raj
  4. Vishal Kumar
  5. Ram murugesan
  6. Ramakrishnan

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Abstract

We dissect the mechanism of SARS-CoV-2 in human lung host from the initial phase of receptor binding to viral replication machinery. We constructed two independent lung protein interactome to reveal the signaling process on receptor activation and host protein hijacking machinery in the pathogenesis of virus. Further, we test the functional role of the hubs derived from both interactome. Most hubs proteins were differentially regulated on SARS-CoV-2 infection. Also, the proteins of viral replication hubs were related with cardiovascular disease, diabetes and hypertension confirming the vulnerability and severity of infection in the risk individual. Additionally, the hub proteins were closely linked with other viral infection, including MERS and HCoVs which suggest similar infection pattern in SARS-CoV-2. We identified five interconnecting cascades between hubs of both networks that show the preparation of optimal environment in the host for viral replication process upon receptor attachment. Interestingly, we propose that seven potential miRNAs, targeting the intermediate phase that connects receptor and viral replication process a better choice as a drug for SARS-CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.20.050138: (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
    We converted all collected interacting human proteins to an official gene/protein symbol using the Uniport database (https://www.uniprot.org/).
    https://www.uniprot.org/
    suggested: (Universal Protein Resource, RRID:SCR_002380)
    The SET-A was further curated to have proteins localized at plasma membrane using Cell surface protein atlas (https://wlab.ethz.ch/cspa/), Human Protein Reference Database (HPRD) (https://www.hprd.org/), and Human Protein Atlas (https://www.proteinatlas.org/) database, assuming SARS-CoV2 structural proteins use these host surface proteins for attachment.
    HPRD
    suggested: None
    https://www.proteinatlas.org/
    suggested: (HPA, RRID:SCR_006710)
    Proteomics DB (https://www.proteomicsdb.org/) and Human Protein Atlas (https://www.proteinatlas.org/) database and integrated using Microsoft access based on the common identifier to create an in-house lung-expressed-gene database.
    https://www.proteomicsdb.org/
    suggested: (ProteomicsDB, RRID:SCR_015562)
    Lung Protein-Protein Interactions: For SET-A and B, we collected human protein-protein interaction data using HumanProteinpedia (http://www.humanproteinpedia.org/), BioGRID (https://thebiogrid.org/)
    HumanProteinpedia
    suggested: None
    http://www.humanproteinpedia.org/
    suggested: (Human Proteinpedia, RRID:SCR_002948)
    BioGRID
    suggested: (BioGrid Australia, RRID:SCR_006334)
    Whereas in the receptor-mediated network, implementing MCODE algorithm was exempted because of its limited number of nodes and edges, which by itself forms hubs.
    MCODE
    suggested: (MCODE, RRID:SCR_015828)
    Mapping the Differential Genes: We searched the gene expression dataset in NCBI Gene Expression Omnibus GEO (http://www.ncbi.nlm.nih.gov/geo/) using various key terms related to SARS-CoV2.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    After quality assessment, the reads were aligned to the human genome (hg19) following the RNA-Seq analysis pipeline to determine the differential expression genes using DESeq with p-value < 0.05.
    DESeq
    suggested: (DESeq, RRID:SCR_000154)

    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: We detected the following sentences addressing limitations in the study:
    Although our approach provides the multi-dimensional view on SARS-CoV2 and host interaction, two major limitations need to be considered, 1) the interaction between SARS-CoV2 spike protein with the host angiotensin (ACE2) receptor is not defined in affinity purification mass spectrometry data. Hence, no direct ACE2 interaction has been established in our interactome. 2) We propose a few miRNAs from our approach, are needed to be validated further for clinical application.

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.04.20.050138v2 on bioRxiv
  3. Version published to 10.1101/2020.04.20.050138v1 on bioRxiv