Respiratory Syncytial Virus co-opts host mitochondrial function to favour infectious virus production

  1. MengJie MengJie Hu
  2. Keith E Schulze
  3. Reena Ghildyal
  4. Darren C Henstridge
  5. Jacek L Kolanowski
  6. Elizabeth J New
  7. Yuning Hong
  8. Alan C Hsu
  9. Philip M Hansbro
  10. Peter AB Wark
  11. Marie A Bogoyevitch
  12. David Andrew Jans  Is a corresponding author
  1. University of Melbourne, Australia
  2. Monash University, Australia
  3. University of Canberra, Australia
  4. Baker Heart and Diabetes Institute, Australia
  5. University of Sydney, Australia
  6. La Trobe University, Australia
  7. University of Newcastle, Australia

Abstract

Although respiratory syncytial virus (RSV) is responsible for more human deaths each year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and redox-sensitive dyes are used to define RSV's impact on host mitochondria for the first time, delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and translocation towards the microtubule-organizing centre. These changes are concomitant with impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-induced lung inflammation. The results establish RSV's unique ability to co-opt host cell mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time as a viable target for therapeutic intervention.

Data availability

Data are being uploaded to Dryad (DOI: https://doi.org/10.5061/dryad.2n3162c). Customised scripts for quantitative analyses of mitochondrial distribution and results are publicly available throughhttps://gitlab.erc.monash.edu.au/mmi/mito

The following data sets were generated

Article and author information

Author details

  1. MengJie MengJie Hu

    Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7362-1452
  2. Keith E Schulze

    Monash Micro Imaging, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Reena Ghildyal

    Centre for Research in Therapeutic Solutions, University of Canberra, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Darren C Henstridge

    Cellular and Molecular Metabolism Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Jacek L Kolanowski

    School of Chemistry, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Elizabeth J New

    School of Chemistry, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuning Hong

    Department of Chemistry and Physics, La Trobe University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Alan C Hsu

    Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6640-0846
  9. Philip M Hansbro

    Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Peter AB Wark

    Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Marie A Bogoyevitch

    Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9745-3716
  12. David Andrew Jans

    Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
    For correspondence
    David.Jans@monash.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5115-4745

Funding

National Health and Medical Research Council (APP1002486)

  • David Andrew Jans

National Health and Medical Research Council (APP1043511)

  • David Andrew Jans

National Health and Medical Research Council (APP1103050)

  • David Andrew Jans

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

Ethics

Animal experimentation: This study was performed in accordance with The ACT Animal Welfare Act (1992) and the Australian Code of Practice for the Care and use of Animals for Scientific Purposes. The study protocol was approved by the Committee for Ethics in Animal Experimentation of the University of Canberra (project reference number CEAE 14-15).

Human subjects: Primary human bronchial epithelial cells (pBECs) were obtained from 4 healthy individuals who had no history of smoking or lung disease, had normal lung function, and gave written, informed consent to participate and have their data published, in accordance with the procedures in accordance with the procedures approved by the University of Newcastle Human Ethics Committee (project reference no. H-163-1205), in keeping with the guidelines of the National Institutes of Health, American Academy of Allergy and Immunology.

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Version history

  1. Received: September 29, 2018
  2. Accepted: June 10, 2019
  3. Accepted Manuscript published: June 27, 2019 (version 1)
  4. Version of Record published: June 28, 2019 (version 2)

Copyright

© 2019, Hu 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. MengJie MengJie Hu
  2. Keith E Schulze
  3. Reena Ghildyal
  4. Darren C Henstridge
  5. Jacek L Kolanowski
  6. Elizabeth J New
  7. Yuning Hong
  8. Alan C Hsu
  9. Philip M Hansbro
  10. Peter AB Wark
  11. Marie A Bogoyevitch
  12. David Andrew Jans
(2019)
Respiratory Syncytial Virus co-opts host mitochondrial function to favour infectious virus production
eLife 8:e42448.
https://doi.org/10.7554/eLife.42448

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