Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

  1. Min Yee
  2. E. David Cohen
  3. Jeannie Haak
  4. Andrew M. Dylag
  5. Michael A. O’Reilly

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Abstract

The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of Ace2 and Tmprss2 mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.22.215962: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: All mice used in this study were of mixed sex and housed in a pathogen-free environment according to a protocol (UCAR2007-121E) approved by the University Committee on Animal Resources at the University of Rochester.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Sections were stained with antibodies against ACE2 (Invitrogen, PA5-47488, Waltham, MA), Scgb1a1 (Sigma, 07-063, St. Louis, MO) and proSP-C (Seven Hills Bioreagents, Cincinnati, OH).
    ACE2
    suggested: (Thermo Fisher Scientific Cat# PA5-47488, RRID:AB_2606505)
    Scgb1a1
    suggested: None
    The membranes were immunoblotted with primary antibodies to ACE2 (Invitrogen, PA5-47488, Waltham, MA), TMPRSS2 (Abcam, ab92323, Cambridge, MA) or β-ACTIN (Sigma, A2066).
    TMPRSS2
    suggested: (Abcam Cat# ab92323, RRID:AB_10585592)
    A2066
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mice: C57BL/6J mice were purchased from the Jackson Laboratories and maintained as an inbred colony.
    C57BL/6J
    suggested: RRID:IMSR_JAX:000664)
    Software and Algorithms
    SentencesResources
    Quantitative RT-PCR: Total RNA was isolated from the lung using Trizol reagent (ThermoFisher Scientific) and reverse transcribed to cDNA using the iScript cDNA synthesis kit (Bio-Rad Laboratories, Hercules, CA).
    Bio-Rad Laboratories
    suggested: (Bio-Rad Laboratories, RRID:SCR_008426)
    Statistical Analysis: Data were evaluated using JMP14 software (SAS Institute, Cary, NC) and graphed as means ± SEM.
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: Thank you for sharing your data.

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 25 and 23. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.07.22.215962 on bioRxiv