1. Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies.
- Author
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Sundaramoorthy, Vinod, Green, Diane, Locke, Kelly, O'Brien, Carmel M., Dearnley, Megan, and Bingham, John
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DENDRITES ,PATHOLOGY ,DOG bites ,RABIES ,PERIPHERAL nervous system ,CENTRAL nervous system ,VIRUS diseases - Abstract
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 its 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. Author summary: Lyssavirus including rabies still causes devastating loss of human life every year and many of its victims are children under the age of 15. Rabies infection causes severe neurological dysfunction in the host resulting in paralysis, cognitive deficits and behavioural abnormalities. The mechanism of how rabies infection induces neurological dysfunction in the host remains unclear. This is because unlike other microbial infections, rabies infection rarely causes neuronal cell death and loss of neurons in the host nervous system. In this study, we show that neurons activate specific axonal self-destruction mechanism during rabies infection to prevent the spread of virus. However, this neuronal self-defense mechanism results in the loss of axons and dendrites, the structural components essential for the functioning of neurons. We further show that axonal degeneration in rabies infection is mediated by SARM1 gene, which has been previously shown to mediate defensive self-destruction of axons and dendrites in the event of neuronal injury. In summary, this study identifies a novel molecular mechanism behind neuronal dysfunction in rabies infection. This study also describes a novel intrinsic anti-viral defence mechanism in neurons, which could influence the pathogenesis of neurotropic viral infections. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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