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

  • 3,739
    views
  • 539
    downloads
  • 46
    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

    Altering the redox status of Chlamydia trachomatis directly impacts its developmental cycle progression

    Vandana Singh, Scot P Ouellette
    Research Article

    Chlamydia trachomatis is an obligate intracellular bacterial pathogen with a unique developmental cycle. It differentiates between two functional and morphological forms: the elementary body (EB) and the reticulate body (RB). The signals that trigger differentiation from one form to the other are unknown. EBs and RBs have distinctive characteristics that distinguish them, including their size, infectivity, proteome, and transcriptome. Intriguingly, they also differ in their overall redox status as EBs are oxidized and RBs are reduced. We hypothesize that alterations in redox may serve as a trigger for secondary differentiation. To test this, we examined the function of the primary antioxidant enzyme alkyl hydroperoxide reductase subunit C (AhpC), a well-known member of the peroxiredoxins family, in chlamydial growth and development. Based on our hypothesis, we predicted that altering the expression of ahpC would modulate chlamydial redox status and trigger earlier or delayed secondary differentiation. Therefore, we created ahpC overexpression and knockdown strains. During ahpC knockdown, ROS levels were elevated, and the bacteria were sensitive to a broad set of peroxide stresses. Interestingly, we observed increased expression of EB-associated genes and concurrent higher production of EBs at an earlier time in the developmental cycle, indicating earlier secondary differentiation occurs under elevated oxidation conditions. In contrast, overexpression of AhpC created a resistant phenotype against oxidizing agents and delayed secondary differentiation. Together, these results indicate that redox potential is a critical factor in developmental cycle progression. For the first time, our study provides a mechanism of chlamydial secondary differentiation dependent on redox status.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats

    Axelle Amen, Randy Yoo ... Matthijs M Jore
    Research Article

    Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf.

    1. Microbiology and Infectious Disease

    Capsular polysaccharide restrains type VI secretion in Acinetobacter baumannii

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

    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.