Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
Keith E Schulze
Monash Micro Imaging, Monash University, Melbourne, Australia
Reena Ghildyal
Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, Australia
Darren C Henstridge
Baker Heart and Diabetes Institute, Melbourne, Australia
Jacek L Kolanowski
School of Chemistry, The University of Sydney, Sydney, Australia
Elizabeth J New
School of Chemistry, The University of Sydney, Sydney, Australia
Yuning Hong
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
Philip M Hansbro
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
Peter AB Wark
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
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.
