High glucose levels increase influenza-associated damage to the pulmonary epithelial-endothelial barrier

Abstract

Diabetes mellitus is a known susceptibility factor for severe influenza virus infections. However, the mechanisms that underlie this susceptibility remain incompletely understood. Here, the effects of high glucose levels on influenza severity were investigated using an in vitro model of the pulmonary epithelial-endothelial barrier as well as an in vivo murine model of type II diabetes. In vitro we show that high glucose conditions prior to IAV infection increased virus-induced barrier damage. This was associated with an increased pro-inflammatory response in endothelial cells and the subsequent damage of the epithelial junctional complex. These results were subsequently validated in vivo. This study provides the first evidence that hyperglycaemia may increase influenza severity by damaging the pulmonary epithelial-endothelial barrier and increasing pulmonary oedema. These data suggest that maintaining long-term glucose control in individuals with diabetes is paramount in reducing the morbidity and mortality associated with influenza virus infections.

Data availability

RNA sequencing data generated in this study are available on the Gene Expression Omnibus repository with accession number GSE145232.

The following data sets were generated

Article and author information

Author details

  1. Katina Dee Hulme

    SCMB, University of Queensland, St Lucia, Australia
    For correspondence
    k.hulme@uq.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1322-0136
  2. Limin Yan

    SCMB, University of Queensland, St Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Rebecca J Marshall

    SCMB, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Conor J Bloxham

    SBMS, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Kyle R Upton

    SCMB, University of Queensland, St Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Sumaira Z Hasnain

    Mater Research Institute, Translational Research Institute, Woolloongabba, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Helle Bielefeldt-Ohmann

    SCMB, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Zhixuan Loh

    School of Biomedical Science, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Katharina Ronacher

    Mater Research Institute, Translational Research Institute, Woolloongabba, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Keng Yih Chew

    SCMB, University of Queensland, St Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Linda A Gallo

    Mater Research Institute, Translational Research Institute, Woolloongabba, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Kirsty Renfree Short

    SCMB, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4963-6184

Funding

National Health and Medical Research Council ((APP1159959)

  • Kirsty Renfree Short

National Health and Medical Research Council

  • Linda A Gallo

National Health and Medical Research Council (DE180100512)

  • Kyle R Upton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the University of Queensland Animal Ethics Committee. (permit no. 071/17).

Reviewing Editor

  1. Melanie Königshoff, University of Colorado, United States

Publication history

  1. Received: March 13, 2020
  2. Accepted: July 17, 2020
  3. Accepted Manuscript published: July 22, 2020 (version 1)
  4. Version of Record published: July 30, 2020 (version 2)

Copyright

© 2020, Hulme et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Katina Dee Hulme
  2. Limin Yan
  3. Rebecca J Marshall
  4. Conor J Bloxham
  5. Kyle R Upton
  6. Sumaira Z Hasnain
  7. Helle Bielefeldt-Ohmann
  8. Zhixuan Loh
  9. Katharina Ronacher
  10. Keng Yih Chew
  11. Linda A Gallo
  12. Kirsty Renfree Short
(2020)
High glucose levels increase influenza-associated damage to the pulmonary epithelial-endothelial barrier
eLife 9:e56907.
https://doi.org/10.7554/eLife.56907

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