1. Microbiology and Infectious Disease

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
https://doi.org/10.7554/eLife.42448
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

Metrics

  • 3,730
    views
  • 536
    downloads
  • 45
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.42448

Categories and tags

Research organism

Further reading

    1. Microbiology and Infectious Disease

    Virus adaptation to heparan sulfate comes with capsid stability tradeoff

    Han Kang Tee, Simon Crouzet ... Caroline Tapparel
    Research Article Updated

    Because of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, we used enterovirus A71 (EV-A71) as the model and demonstrated that, unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167 G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes. We experimentally confirmed that this pH-independent entry is not associated with the use of HS as an attachment receptor but rather with compromised capsid stability. We then extended these findings to another HS-dependent strain. In summary, our data indicate that the acquisition of capsid mutations conferring affinity for HS comes together with decreased capsid stability and allows EV-A71 to enter the cell via a pH-independent pathway. This pH-independent entry mechanism boosts viral replication in cell lines but may prove deleterious in vivo, especially for enteric viruses crossing the acidic gastric environment before reaching their primary replication site, the intestine. Our study thus provides new insight into the mechanisms underlying the in vivo attenuation of HS-binding EV-A71 strains. Not only are these viruses hindered in tissues rich in HS due to viral trapping, as generally accepted, but our research reveals that their diminished capsid stability further contributes to attenuation in vivo. This underscores the complex relationship between HS-binding, capsid stability, and viral fitness, where increased replication in cell lines coincides with attenuation in harsh in vivo environments like the gastrointestinal tract.

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease

    Aminoglycoside tolerance in Vibrio cholerae engages translational reprogramming associated with queuosine tRNA modification

    Louna Fruchard, Anamaria Babosan ... Zeynep Baharoglu
    Research Article

    Tgt is the enzyme modifying the guanine (G) in tRNAs with GUN anticodon to queuosine (Q). tgt is required for optimal growth of Vibrio cholerae in the presence of sub-lethal aminoglycoside concentrations. We further explored here the role of the Q34 in the efficiency of codon decoding upon tobramycin exposure. We characterized its impact on the overall bacterial proteome, and elucidated the molecular mechanisms underlying the effects of Q34 modification in antibiotic translational stress response. Using molecular reporters, we showed that Q34 impacts the efficiency of decoding at tyrosine TAT and TAC codons. Proteomics analyses revealed that the anti-SoxR factor RsxA is better translated in the absence of tgt. RsxA displays a codon bias toward tyrosine TAT and overabundance of RsxA leads to decreased expression of genes belonging to SoxR oxidative stress regulon. We also identified conditions that regulate tgt expression. We propose that regulation of Q34 modification in response to environmental cues leads to translational reprogramming of transcripts bearing a biased tyrosine codon usage. In silico analysis further identified candidate genes which could be subject to such translational regulation, among which DNA repair factors. Such transcripts, fitting the definition of modification tunable transcripts, are central in the bacterial response to antibiotics.

    1. Microbiology and Infectious Disease

    Capsular Polysaccharide Restrains Type VI Secretion in Acinetobacter baumannii

    Nicolas Flaugnatti, Loriane Bader ... Melanie Blokesch
    Research Article

    The type VI secretion system (T6SS) is a sophisticated, contact-dependent nanomachine involved in interbacterial competition. To function effectively, the T6SS must penetrate the membranes of both attacker and target bacteria. Structures associated with the cell envelope, like polysaccharides chains, can therefore introduce spatial separation and steric hindrance, potentially affecting the efficacy of the T6SS. In this study, we examined how the capsular polysaccharide (CPS) of Acinetobacter baumannii affects T6SS's antibacterial function. Our findings show that the CPS confers resistance against T6SS-mediated assaults from rival bacteria. Notably, under typical growth conditions, the presence of the surface-bound capsule also reduces the efficacy of the bacterium's own T6SS. This T6SS impairment is further enhanced when CPS is overproduced due to genetic modifications or antibiotic treatment. Furthermore, we demonstrate that the bacterium adjusts the level of the T6SS inner tube protein Hcp according to its secretion capacity, by initiating a degradation process involving the ClpXP protease. Collectively, our findings contribute to a better understanding of the dynamic relationship between T6SS and CPS and how they respond swiftly to environmental challenges.