Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies.
Animals
Armadillo Domain Proteins
/ genetics
Axonal Transport
/ physiology
Axons
/ metabolism
Cytoskeletal Proteins
/ genetics
Disease Models, Animal
Ganglia, Spinal
/ virology
Lyssavirus
/ pathogenicity
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurites
/ metabolism
Neurons
/ metabolism
Rabies
/ metabolism
Rabies virus
/ metabolism
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
26
09
2019
accepted:
22
01
2020
revised:
28
02
2020
pubmed:
19
2
2020
medline:
6
6
2020
entrez:
19
2
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32069324
doi: 10.1371/journal.ppat.1008343
pii: PPATHOGENS-D-19-01797
pmc: PMC7048299
doi:
Substances chimiques
Armadillo Domain Proteins
0
Cytoskeletal Proteins
0
SARM1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008343Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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