Adenosine A2A Receptor (A 2A R) agonists improve survival in K28-hACE2 mice following SARS CoV-2 infection

  1. Barbara J. Mann
  2. Preeti Chhabra
  3. Mingyang Ma
  4. Savannah G. Brovero
  5. Marieke K. Jones
  6. Joel Linden
  7. Kenneth L. Brayman

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Abstract

Effective and available therapies for the treatment of COVID-19 disease are limited. Apadenoson is a highly potent selective anti-inflammatory adenosine A 2A receptor (A 2A R) agonist and potential treatment option for COVID-19 patients. Apadenoson, when administered after infection with SARS CoV-2, was found to decrease weight loss, improve clinical symptoms, reduce levels of a several proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and promote increased survival in K18hACE2 transgenic mice. Of note, administering apadenoson after, but not prior to Covid-19 infection, caused a rapid decrease in lung viral burden. The work presented provides the foundation for further examination of these drugs as a therapy option for COVID-19.

Summary

Apadenoson therapy improves COVID-19 outcome

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    SciScore for 10.1101/2022.02.25.481997: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: All mouse work was approved by the University’s Institutional Animal Care and Use Committee and all procedures were performed in the University’s certified animal Biosafety Level Three laboratory, which is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, International (AAALAC).
    Sex as a biological variableInfection and treatment: Twenty-four hours prior to infecting Tg(K18-hACE2)2Prlmn (Jackson Laboratories) male mice with SARS CoV-2, primed 7-day Alzet® osmotic pumps (Durect, Cuperton, CA) containing saline or drug were implanted subcutaneously (McCray et al., 2007).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    To visualize virus in the lungs, slides were stained with SARS-CoV2 specific anti-nucleoprotein antibody (Cat. No. 9099, ProSci, Poway, CA) as per manufacturer’s instructions and then scanned at 20X magnification.
    anti-nucleoprotein
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Infection and treatment: Twenty-four hours prior to infecting Tg(K18-hACE2)2Prlmn (Jackson Laboratories) male mice with SARS CoV-2, primed 7-day Alzet® osmotic pumps (Durect, Cuperton, CA) containing saline or drug were implanted subcutaneously (McCray et al., 2007).
    Tg(K18-hACE2)2Prlmn
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical differences in weight loss and clinical scores by treatment group were determined using linear mixed models accounting for day post-infection and the day the mouse died (Ime4 and ImerTest packages (Bates et al., 2015)(Kuznetsova et al., 2017) in R (R Core Team 2021).
    ImerTest
    suggested: None
    Statistical changes in cytokine levels were analyzed using Welch’s ANOVA followed by Dunnett’s T3 multiple comparisons (Graphpad Prism 9.0).
    Graphpad
    suggested: (GraphPad, RRID:SCR_000306)
    The percentage of lung tissue infected with virus was calculated (ImageJ, version 1.53K).
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)

    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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  2. Version published to 10.1101/2022.02.25.481997v2 on bioRxiv
  3. Version published to 10.1101/2022.02.25.481997v1 on bioRxiv