Rabies is a lethal neurotrophic virus which spreads exclusively within interconnected neurons in the host nervous system by transferring across neuronal junctions (synapses). This ability to trans-synaptically transfer between neurons is also shared by other neurotropic viruses such as herpes simplex virus, varicella zoster virus, measles, nipah, west nile virus and poliovirus. Spread of viruses in the nervous system by trans-synaptic transmission cause acute as well as chronic long-term impact on the neurological functioning, if not fatal. Alternatively, the specific trans-synaptic transfer ability of attenuated rabies virus is also exploited beneficially as an anatomical neuronal circuit tracer and as a potential vector system to carry therapeutics to the brain. However, the mechanisms that facilitate the transfer of rabies and other neurotropic viruses across the synapse is unknown. While the envelope protein (glycoprotein) of rabies virus is responsible for this trans-synaptic transmission, the specific neuronal receptors and associated ultrastructural changes occurring at the neuronal synapse to facilitate viral transfer remains unknown.
In this study, we employed advanced confocal imaging techniques in high-containment PC3 laboratories to study trans-synaptic transfer of rabies virus in neurons. Using ex-vivo neuronal models, we performed ultrastructural investigation of rabies virus transfer between neurons in live and fixed cultures. In these studies, we identified novel trans-synaptic transfer mechanisms utilised by highly-neuroinvasive and low-neuroinvasive rabies strains in neurons. Interestingly, we also discovered novel abilities of rabies virus glycoprotein to control the signalling pathways of cell adhesion molecules and modify synaptic architecture in neurons to enable virus transfer. These studies identified new information about how rabies spreads through the nervous system enabling future approaches for rabies treatment and design next-generation rabies-derived vector systems for brain research and drug delivery. In addition, the findings from this study provide valuable and transferable knowledge about how viruses could manipulate the biology of synapses in the nervous system to enable efficient transmission. Targeting these mechanisms could identify treatment strategies to protect the nervous system during viral infections.