Rabies is a neglected zoonosis caused by neurotropic viruses of the genus Lyssavirus, of which RABV is the best characterized. RABV has a worldwide distribution and is predominantly transmitted to humans through the bite of infected dogs. RABV causes a fatal encephalitis, and infected patients may exhibit symptoms of classic furious rabies or develop paralytic rabies leading to coma. However, the neuroanatomical basis of behavioral changes following RABV infection is not well understood. Since RABV disrupts immune pathways in neurons and glial cells to invade the brain unnoticed, the working hypothesis is that RABV interferes with neuroglial communication to abrogate the host antiviral response in the neurons, which may lead to impaired serotonergic-cholinergic signaling and consequently altered neurobehavior. Accordingly, within the framework of this PhD project, the specific objectives are to:
1. investigate whether RABV can infect cholinergic and serotonergic neurons and understand how infection affects their communication,
2. describe which structures, inflammatory and neural signaling pathways are affected during the spread of RABV in the central nervous system (CNS),
3. unravel how RABV infection affects behavior.
These objectives will be achieved through a comprehensive spatiotemporal in vivo analysis of infection dynamics in the brain using behavioral assays, whole brain imaging, and spatial transcriptomics, combined with a precise and individualized assessment of each component of the infection process at a single cell resolution based on reverse genetics, brain-on-chip networks, midbrain organoids, and single cell transcriptomics. In the end, the results obtained within this project will improve the understanding of rabies neuropathogenesis that links molecular mechanisms to a complete clinical-behavioral picture, which is key to developing and improving rabies treatment methods in humans. In addition, this project will provide insights into the gene
