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Mitochondrial dysfunction in rabies virus infection of neurons

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Abstract

Infection with the challenge virus standard-11 (CVS) strain of fixed rabies virus induces neuronal process degeneration in adult mice after hindlimb footpad inoculation. CVS-induced axonal swellings of primary rodent dorsal root ganglion neurons are associated with 4-hydroxy-2-nonenal protein adduct staining, indicating a critical role of oxidative stress. Mitochondrial dysfunction is the major cause of oxidative stress. We hypothesized that CVS infection induces mitochondrial dysfunction leading to oxidative stress. We investigated the effects of CVS infection on several mitochondrial parameters in different cell types. CVS infection significantly increased maximal uncoupled respiration and complex IV respiration and complex I and complex IV activities, but did not affect complex II–III or citrate synthase activities. Increases in complex I activity, but not complex IV activity, correlated with susceptibility of the cells to CVS infection. CVS infection maintained coupled respiration and rate of proton leak, indicating a tight mitochondrial coupling. Possibly as a result of enhanced complex activity and efficient coupling, a high mitochondrial membrane potential was generated. CVS infection reduced the intracellular ATP level and altered the cellular redox state as indicated by a high NADH/NAD+ ratio. The basal production of reactive oxygen species (ROS) was not affected in CVS-infected neurons. However, a higher rate of ROS generation occurred in CVS-infected neurons in the presence of mitochondrial substrates and inhibitors. We conclude that CVS infection induces mitochondrial dysfunction leading to ROS overgeneration and oxidative stress.

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Acknowledgements

This work was supported by Canadian Institutes of Health Research / Manitoba Regional Partnership Program with the Manitoba Health Research Council (to A.C. Jackson and P. Fernyhough) and the St. Boniface Hospital Research Foundation (to P. Fernyhough). We thank Dr. Ali Saleh for assistance with the ANOVA statistical analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada

    Thamir Alandijany & Alan C. Jackson

  2. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, 21589, Jeddah, 80324, Saudi Arabia

    Thamir Alandijany

  3. Department of Internal Medicine (Neurology), University of Manitoba, Winnipeg, Manitoba, R3A 1R9, Canada

    Wafa Kammouni & Alan C. Jackson

  4. Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6, Canada

    Subir K. Roy Chowdhury & Paul Fernyhough

  5. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, R3E 0T6, Canada

    Paul Fernyhough

  6. Health Sciences Centre, GF-543, 820 Sherbrook Street, Winnipeg, Manitoba, Canada, R3A 1R9

    Alan C. Jackson

Authors
  1. Thamir Alandijany
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  2. Wafa Kammouni
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  3. Subir K. Roy Chowdhury
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  4. Paul Fernyhough
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  5. Alan C. Jackson
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Corresponding author

Correspondence to Alan C. Jackson.

Additional information

Submitted to the Journal of NeuroVirology (NJIV-D-13-00082) on August 2, 2013; Revised and resubmitted on September 20, 2013

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Alandijany, T., Kammouni, W., Roy Chowdhury, S.K. et al. Mitochondrial dysfunction in rabies virus infection of neurons. J. Neurovirol. 19, 537–549 (2013). https://doi.org/10.1007/s13365-013-0214-6

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  • DOI: https://doi.org/10.1007/s13365-013-0214-6

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