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Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies

Sundaramoorthy, Vinod, Green, Diane, Locke, Kelly, O'Brien, Carmel M., Dearnley, Megan and Bingham, John 2020, Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies, Plos pathogens, vol. 16, no. 2, pp. 1-20, doi: 10.1371/journal.ppat.1008343.r004.

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Title Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies
Author(s) Sundaramoorthy, VinodORCID iD for Sundaramoorthy, Vinod orcid.org/0000-0001-6309-8031
Green, Diane
Locke, Kelly
O'Brien, Carmel M.
Dearnley, Megan
Bingham, John
Journal name Plos pathogens
Volume number 16
Issue number 2
Article ID e1008343
Start page 1
End page 20
Total pages 20
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2020-02
ISSN 1553-7366
1553-7374
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
WALLERIAN DEGENERATION
PARALYTIC RABIES
NEUROPATHOGENETIC MECHANISMS
SELF-DESTRUCTION
NERVOUS-SYSTEM
VIRUS
INJURY
ACTIVATION
PATHOLOGY
NEURONS
Summary Neurotropic viral infections continue to pose a serious threat to human and animal wellbeing. Host responses combatting the invading virus in these infections often cause irreversible damage to the nervous system, resulting in poor prognosis. Rabies is the most lethal neurotropic virus, which specifically infects neurons and spreads through the host nervous system by retrograde axonal transport. The key pathogenic mechanisms associated with rabies infection and axonal transmission in neurons remains unclear. Here we studied the pathogenesis of different field isolates of lyssavirus including rabies using ex-vivo model systems generated with mouse primary neurons derived from the peripheral and central nervous systems. In this study, we show that neurons activate selective and compartmentalized degeneration of their axons and dendrites in response to infection with different field strains of lyssavirus. We further show that this axonal degeneration is mediated by the loss of NAD and calpain-mediated digestion of key structural proteins such as MAP2 and neurofilament. We then analysed the role of SARM1 gene in rabies infection, which has been shown to mediate axonal self-destruction during injury. We show that SARM1 is required for the accelerated execution of rabies induced axonal degeneration and the deletion of SARM1 gene significantly delayed axonal degeneration in rabies infected neurons. Using a microfluidic-based ex-vivo neuronal model, we show that SARM1-mediated axonal degeneration impedes the spread of rabies virus among interconnected neurons. However, this neuronal defense mechanism also results in the pathological loss of axons and dendrites. This study therefore identifies a potential host-directed mechanism behind neurological dysfunction in rabies infection. This study also implicates a novel role of SARM1 mediated axonal degeneration in neurotropic viral infection. 
Language eng
DOI 10.1371/journal.ppat.1008343.r004
Indigenous content off
Field of Research 0605 Microbiology
1107 Immunology
1108 Medical Microbiology
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30136314

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.