Increased sensitivity of SARS-CoV-2 to type III interferon in human intestinal epithelial cells

  1. Carmon Kee
  2. Camila Metz-Zumaran
  3. Patricio Doldan
  4. Cuncai Guo
  5. Megan L. Stanifer
  6. Steeve Boulant

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Abstract

The coronavirus SARS-CoV-2 caused the COVID-19 global pandemic leading to 3.5 million deaths worldwide as of June 2021. The human intestine was found to be a major viral target which could have a strong impact on virus spread and pathogenesis since it is one of the largest organs. While type I interferons (IFNs) are key cytokines acting against systemic virus spread, in the human intestine type III IFNs play a major role by restricting virus infection and dissemination without disturbing homeostasis. Recent studies showed that both type I and III IFNs can inhibit SARS-CoV-2 infection, but it is not clear if one IFN controls SARS-CoV-2 infection of the human intestine better or with a faster kinetics. In this study, we could show that both type I and III IFNs possess antiviral activity against SARS-CoV-2 in human intestinal epithelial cells (hIECs), however type III IFN is more potent. Shorter type III IFN pretreatment times and lower concentrations were required to efficiently reduce virus load when compared to type I IFNs. Moreover, type III IFNs significantly inhibited SARS-CoV-2 even 4 hours post-infection and induced a long-lasting antiviral effect in hIECs. Importantly, the sensitivity of SARS-CoV-2 to type III IFNs was virus-specific since type III IFN did not control VSV infection as efficiently. Together these results suggest that type III IFNs have a higher potential for IFN-based treatment of SARS-CoV-2 intestinal infection as compared to type I IFNs.

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  1. ScreenIT

    SciScore for 10.1101/2021.06.14.448464: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Primary antibodies beta-Actin (Sigma #5441) and phospho STAT1 (BD Transductions #612233) were diluted in the same blocking buffer and incubated overnight at 4°C.
    beta-Actin
    suggested: None
    phospho STAT1
    suggested: (BD Biosciences Cat# 612233, RRID:AB_399556)
    Anti-mouse antibodies coupled with horseradish peroxidase (GE Healthcare #NA934V) were used at 1:5000 dilution in blocking buffer and incubated at RT for 1 hour with rocking.
    Anti-mouse
    suggested: None
    Mouse monoclonal antibody against SARS-CoV-2 Nucleocapsid protein (Sino biologicals MM05) was diluted in 1% BSA-phosphate-buffered saline (PBS) and incubated for 1h at RT.
    SARS-CoV-2 Nucleocapsid protein
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Viral infections: All SARS-CoV-2 infections were performed with a multiplicity of infection of 0.04 as determined in Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    Statistics and computational analyses and statistics: All statistical analysis was performed either by Ordinary one way ANOVA Dunnett’s multiple comparison test or by a two-tailed unpaired t-test with Welch’s correlation (specified in figure legend) using the GraphPad Prism software package.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    These masks were used on CellProfiler 3.1.9 to measure the intensity of the conjugated secondary antibodies in each nucleus.
    CellProfiler
    suggested: None

    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: 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: 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 10.1101/2021.06.14.448464v1 on bioRxiv