Respiratory Syncytial Virus co-opts host mitochondrial function to favour infectious virus production
- University of Melbourne, Australia
- Monash University, Australia
- University of Canberra, Australia
- Baker Heart and Diabetes Institute, Australia
- University of Sydney, Australia
- La Trobe University, Australia
- 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
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Data from: Respiratory Syncytial Virus co-opts host mitochondrial function to favour infectious virus productionDryad Digital Repository, doi:10.5061/dryad.j1fd7.
Article and author information
Author details
MengJie MengJie Hu
Marie A Bogoyevitch
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.
Reviewing Editor
- Agnieszka Chacinska, University of Warsaw, Poland
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.
Version history
- Received: September 29, 2018
- Accepted: June 10, 2019
- Accepted Manuscript published: June 27, 2019 (version 1)
- 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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Respiratory Syncytial Virus co-opts host mitochondrial function to favour infectious virus production
eLife 8:e42448.
https://doi.org/10.7554/eLife.42448
Further reading
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Antimicrobial resistance (AMR) poses a significant threat to human health. Although vaccines have been developed to combat AMR, it has proven challenging to associate specific vaccine antigens with AMR. Bacterial plasmids play a crucial role in the transmission of AMR. Our recent research has identified a group of bacterial plasmids (specifically, IncHI plasmids) that encode large molecular mass proteins containing bacterial immunoglobulin-like domains. These proteins are found on the external surface of the bacterial cells, such as in the flagella or conjugative pili. In this study, we show that these proteins are antigenic and can protect mice from infection caused by an AMR Salmonella strain harboring one of these plasmids. Furthermore, we successfully generated nanobodies targeting these proteins, that were shown to interfere with the conjugative transfer of IncHI plasmids. Considering that these proteins are also encoded in other groups of plasmids, such as IncA/C and IncP2, targeting them could be a valuable strategy in combating AMR infections caused by bacteria harboring different groups of AMR plasmids. Since the selected antigens are directly linked to AMR itself, the protective effect extends beyond specific microorganisms to include all those carrying the corresponding resistance plasmids.
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Canine distemper virus (CDV) belongs to morbillivirus, including measles virus (MeV) and rinderpest virus, which causes serious immunological and neurological disorders in carnivores, including dogs and rhesus monkeys, as recently reported, but their vaccines are highly effective. The attachment glycoprotein hemagglutinin (CDV-H) at the CDV surface utilizes signaling lymphocyte activation molecule (SLAM) and Nectin-4 (also called poliovirus-receptor-like-4; PVRL4) as entry receptors. Although fusion models have been proposed, the molecular mechanism of morbillivirus fusion entry is poorly understood. Here, we determined the crystal structure of the globular head domain of CDV-H vaccine strain at 3.2 Å resolution, revealing that CDV-H exhibits a highly tilted homodimeric form with a six-bladed β-propeller fold. While the predicted Nectin-4-binding site is well conserved with that of MeV-H, that of SLAM is similar but partially different, which is expected to contribute to host specificity. Five N-linked sugars covered a broad area of the CDV-H surface to expose receptor-binding sites only, supporting the effective production of neutralizing antibodies. These features are common to MeV-H, although the glycosylation sites are completely different. Furthermore, real-time observation using high-speed atomic force microscopy revealed highly mobile features of the CDV-H dimeric head via the connector region. These results suggest that sugar-shielded tilted homodimeric structure and dynamic conformational changes are common characteristics of morbilliviruses and ensure effective fusion entry and vaccination.
