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Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains

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Abstract

Rabies is a fatal encephalitis caused by the Rabies lyssavirus (RABV). The presence of minimal neuropathological changes observed in rabies indicates that neuronal dysfunction, rather than neuronal death contributes to the fatal outcome. The role of mitochondrial changes has been suggested as a possible mechanism for neuronal dysfunction in rabies. However, these findings are mostly based on studies that have employed experimental models and laboratory-adapted virus. Studies on brain tissues from naturally infected human and animal hosts are lacking. The current study investigated the role of mitochondrial changes in rabies by morphological, biochemical and proteomic analysis of RABV-infected human and canine brains. Morphological analysis showed minimal inflammation with preserved neuronal and disrupted mitochondrial structure in both human and canine brains. Proteomic analysis revealed involvement of mitochondrial processes (oxidative phosphorylation, cristae formation, homeostasis and transport), synaptic proteins and autophagic pathways, with over-expression of subunits of mitochondrial respiratory complexes. Consistent with these findings, human and canine brains displayed elevated activities of complexes I (p < 0.05), IV (p < 0.05) and V (p < 0.05). However, this did not result in elevated ATP production (p < 0.0001), probably due to lowered mitochondrial membrane potential as noted in RABV-infected cells in culture. These could lead to mitochondrial dysfunction and mitophagy as indicated by expression of FKBP8 (p < 0.05) and PINK1 (p < 0.001)/PARKIN (p > 0.05) and ensuing autophagy, as shown by the status of LCIII (p < 0.05), LAMP1 (p < 0.001) and pertinent ultrastructural markers. We propose that altered mitochondrial bioenergetics and cristae architecture probably induce mitophagy, leading to autophagy and consequent neuronal dysfunction in rabies.

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Data Availability

The MS data presented in the current manuscript have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository [79] with the dataset identifier PXD020789 (http://www.ebi.ac.uk/pride).

Abbreviations

CI:

Complex I

CII:

Complex II

CIII:

Complex III

CIV:

Complex IV

CV:

Complex V

CVS:

Challenge Virus Standard

EM:

Electron microscopy

HE:

Haematoxylin and eosin

MS:

Mass spectrometry

RABV:

Rabies lyssavirus

ROS:

Reactive oxygen species

RRID:

Research resource identifier

SV:

Street virus

TMT:

Tandem mass tag

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Acknowledgements

The technical help provided by Mr. Ramesh, Ms. Rashmi S and Mr. Satheesh from the Electron Microscopy Facility, Department of Neuropathology, NIMHANS is gratefully acknowledged. The assistance of Mr. Shivaji Rao and Mrs. Rajasakti from the Human Brain Tissue Repository, NIMHANS with the histopathology experiments is gratefully acknowledged. The authors acknowledge the help of Dr. Gajanan Sathe, Institute of Bioinformatics, Bangalore for his help with analysis of MS data.

Funding

PKH is supported through the project titled “Testing of blood samples for rabies virus neutralizing antibodies by RFFIT” (Grant no. OTHERS/001/107/2014/00713), at the department of Neurovirology, NIMHANS, Bangalore, India, funded by Cadila Pharmaceuticals, India (Principal Investigator-RSM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Neurovirology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

    Pulleri Kandi Harsha & Reeta S. Mani

  2. Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

    Sathyanarayanan Ranganayaki & M. M. Srinivas Bharath

  3. Mission Rabies, Goa, India

    Gowri Yale

  4. Manipal Academy of Higher Education, Manipal, India

    Gourav Dey

  5. Institute of Bioinformatics, Bangalore, India

    Gourav Dey & Kiran K. Mangalaparthi

  6. Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

    Anusha Yarlagadda, B. K. Chandrasekhar Sagar & Anita Mahadevan

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Contributions

PKH: Methodology; data curation; validation; formal analysis; writing—original draft preparation, SR: conceptualization; data curation; writing—original draft preparation, GY: resources, KKM: methodology; data curation, GD: methodology; data curation, AY; methodology, BKCS: analysis, AM: conceptualization; data analysis; writing-review and editing; resources; supervision, MMSB: conceptualization; writing-review and editing, supervision; project administration, RSM: conceptualization; writing-review and editing, supervision; project administration; resources.

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Correspondence to M. M. Srinivas Bharath or Reeta S. Mani.

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Harsha, P.K., Ranganayaki, S., Yale, G. et al. Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains. Neurochem Res 47, 1610–1636 (2022). https://doi.org/10.1007/s11064-022-03556-6

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