Bacteriophage-Derived Double-Stranded RNA Exerts Anti-SARS-CoV-2 Activity In Vitro and in Golden Syrian Hamsters In Vivo

  1. Kristine Vaivode
  2. Irina Verhovcova
  3. Dace Skrastina
  4. Ramona Petrovska
  5. Madara Kreismane
  6. Daira Lapse
  7. Zane Kalnina
  8. Kristine Salmina
  9. Diana Rubene
  10. Dace Pjanova

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Abstract

Bacteriophage-derived dsRNA, known as Larifan, is a nationally well-known broad-spectrum antiviral medication. This study aimed to ascertain the antiviral activity of Larifan against the novel SARS-CoV-2 virus. Larifan’s effect against SARS-CoV-2 in vitro was measured in human lung adenocarcinoma (Calu3) and primary human small airway epithelial cells (HSAEC), and in vivo in the SARS-CoV-2 infection model in golden Syrian hamsters. Larifan inhibited SARS-CoV-2 replication both in vitro and in vivo. Viral RNA copy numbers and titer of infectious virus in the supernatant of Calu3 cells dropped significantly: p = 0.0296 and p = 0.0286, respectively. A reduction in viral RNA copy number was also observed in HSAEC, especially when Larifan was added before infection (p = 0.0218). Larifan markedly reduced virus numbers in infected hamsters’ lungs post-infection, with a more pronounced effect after intranasal administration (p = 0.0032). The administration of Larifan also reduced the amount of infections virus titer in the lungs (p = 0.0039). Improvements in the infection-induced pathological lesion severity in the lungs of animals treated with Larifan were also demonstrated. The inhibition of SARS-CoV-2 replication in vitro and the reduction in the viral load in the lungs of infected hamsters treated with Larifan alongside the improved lung histopathology suggests a potential use of Larifan in also controlling the COVID-19 disease in humans.

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  1. Version published to 10.3390/ph15091053
  2. Version published to 10.1101/2022.01.22.477073v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2022.01.22.477073: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The experimental procedures in animals were approved by the National animal welfare and ethics committee (permit no. 124/2021) and were performed in compliance with the Directive 2010/63/EU as adopted in the national legislation.
    Sex as a biological variableIn total, 24 naïve 9-10 weeks old specific pathogen free (SPF) male Golden Syrian hamsters (strain HsdHan®:Aura) were purchased from Envigo (US) and after introduction they were single-housed in individually ventilated cages GR900 (Tecniplast, Italy), HEPA-ventilated by SmartFlow air handling unit (Tecniplast, Italy) at 75 air changes per hour in a negative pressure mode.
    Randomizationnot detected.
    BlindingTissue sections (7 μm) were stained with hematoxylin and eosin stains and analyzed blindly for lung damage by a certified pathologist.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: Vero E6 cells (African green monkey kidney, ATCC CRL-1586) and Calu3 (human lung adenocarcinoma cells, ATCC HTB-55) were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 1% L-glutamine and 1% bicarbonate (all from Gibco).
    Vero E6
    suggested: None
    Infection of cells with SARS-CoV-2 and treatment with Larifan: Calu3 and HSAEC cells were grown to a monolayer in 6-well plates.
    HSAEC
    suggested: None
    Software and Algorithms
    SentencesResources
    Absolute quantifications of virus RNA copies were estimated by modelling a Poisson distribution using QuantaSoft™ analysis software version 1.7 (Bio-Rad).
    QuantaSoft™ analysis
    suggested: None
    Statistical analysis: GraphPad Prism (GraphPad Software, Inc.) was used to perform statistical analysis.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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.

    About SciScore

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  4. Version published to 10.1101/2022.01.22.477073v1 on bioRxiv