Rabies (lyssavirus) is a deadly zoonotic virus that has the unique ability to infect the host nervous system and transfer across neural junctions known as synapses. This mode of transmission allows the virus to evade detection from the immune system and leads to irreversible damage to the nervous system. Although the virus has existed over several centuries, a lot is still unknown about the pathogenesis of the virus and the signaling pathways responsible for its trans-synaptic transmission. It is known that the rabies viral glycoprotein is essential in its movement across the synapse, but the neuronal proteins that are influenced by the glycoprotein to increase synapse formation is still unknown.
In this study we used advanced confocal microscopy to analyse the trans-synaptic transfer of the virus in high and low neuroinvasive strains. The highly invasive strain showed a more efficient trans-synaptic transmission of the virus, an increase in filipodia-like structures in the synaptic membrane, and an increase in synaptogenesis. We are now performing proteomic analyses to study and compare the viral glycoprotein in both strains and their associated interactomes. Super-resolution microscopy will then provide insight into the viral glycoprotein and its interacting partners at the synapse. This will allow us to identify what neuronal proteins may be responsible for the increase in synapse formation in the highly neuroinvasive strain.
This will provide novel insight into new signaling pathways and molecules that are involved in synaptogenesis. The identification of the neural proteins involved in trans-synaptic transmission of the virus could also provide valuable knowledge to develop future therapeutics for rabies treatment. This information could also be used to design next generation rabies inspired therapeutics to increase synapse formation in neurodegenerative and neurodevelopmental diseases that occur as a result of synapse degeneration or deformation.