Comparing Expression of OAS-RNaseL Pathway-Related Genes in SARS-CoV-2 and Similar Viruses

  1. Nikhil Chakravarty
  2. Penelope A. Edillor
  3. Andy P. Huang
  4. Giovanni A. Torres
  5. Manal T. Usmani
  6. Pavan Kadandale

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Abstract

The COVID-19 pandemic, caused by the virus SARS-CoV-2, has been a major public health emergency and has caused millions of deaths worldwide to date. Due to the novel nature of the virus, efforts across the world are underway to better understand the molecular pathogenesis of SARS-CoV-2 and how it interacts with host immune responses. One important branch of the innate immune response, the interferon system, triggers the expression of many effector mechanisms known to be powerful antagonists against many pathogenic viruses. One such interferon stimulated mechanism is the OAS-RNaseL pathway, which is known to trigger the degradation of viral RNA in infected host cells. Our study seeks to utilize publicly available transcriptomic data to analyze the host cell OAS-RNaseL pathway to SARS-CoV-2 infection. We hoped to gain an understanding of the importance of the pathway in controlling SARS-CoV-2 infection and whether or not the pathway could be exploited therapeutically. Our findings demonstrated that upregulation of OAS-RNaseL pathway genes in response to SARS-CoV-2 infection varies based on cell type and appeared to correlate with ACE2 receptor expression. Pathway responses to other viruses like SARS-CoV and MERS-CoV were found to parallel those to SARS-CoV-2, suggesting common response patterns by the pathway to these viruses. Overall, these results demonstrate that the OAS-RNaseL pathway could contribute to control of SARS-CoV-2 infection. Further studies on various mechanistic actions by the pathway would need to be conducted to fully understand its role in host defense and therapy.

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    SciScore for 10.1101/2021.04.29.442063: (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
    RNA sequencing data collection: The NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/) was searched for RNA-sequencing datasets from experiments with cell cultures or samples infected with SARS-CoV-2 or other viruses between June and November 2020.
    BioProject
    suggested: (NCBI BioProject, RRID:SCR_004801)
    RNA sequencing data analysis: The SRA files were extracted by fastq-dump utility of an SRA Toolkit, FASTQ Sequencing, file was uploaded to Galaxy web platform (usegalaxy.org), which was used to perform further data analysis29.
    Galaxy
    suggested: (Galaxy, RRID:SCR_006281)
    Next, the Trimmomatic function with the singleend read setting was used to remove Illumina sequencing adapters, remove sequence ends with average quality scores lower than 20 over four bases using sliding window trimming, and remove any sequences smaller than 25 base pairs.
    Trimmomatic
    suggested: (Trimmomatic, RRID:SCR_011848)
    The HISAT2 function was used for each trimmed output to align sequences in each dataset to the genome of their respective organisms.
    HISAT2
    suggested: (HISAT2, RRID:SCR_015530)
    To observe changes in gene expression under different experimental conditions, the DESeq2 function was used to compare counts tables from mock treated datasets and experimentally treated datasets.
    DESeq2
    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:
    The limitations of comparing different cell lines, such as not taking into account differing viral tropism, likely contributed to this. Further studies through direct experimentation would be necessary to gain a more complete picture of the relationship between the OAS-RNaseL mechanism and the ability for SARS-CoV-2 to replicate. Recent studies, involving the use of RNaseL knockout strains of A549-ACE2, have revealed that the deletion of RNaseL results in significantly increased SARS-CoV-2 replication, which is a promising development44. Combined with the clinical finding that increased OAS1 expression positively correlated with better COVID-19 outcomes45, the ability of the OAS-RNaseL pathway to induce protective immune mechanisms such as apoptosis make it an attractive target for continued study as a SARS-CoV-2 therapeutic. Entry Receptor Abundance and the Presence of Antiviral Proteins Influence IFN Expression Pattern: One question that arises from our results relates to the expression pattern of type I and II IFNs, which have been shown to stimulate the expression of antiviral effectors including the OAS-RNaseL pathway7,8. We observed significant differences in induction strength for type I and II IFNs as well as associated ISGs across the different analyzed cell lines. Previous studies have also found divergent IFN induction levels between lung and intestinal epithelial cells in the context of SARS-CoV-2, though the causation is currently unknown46. Our analysis of ACE2 ...

    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.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.04.29.442063 on bioRxiv