Whole brain visualisation of the neuroinflammatory response during acute neurotropic flavivirus infection and its implications for virus-induced neurodegeneration

Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV) and Zika Virus (ZIKV) can enter and infect the central nervous system, potentially leading to lethal encephalitis. Furthermore, survivors often suffer from chronic neurological complications, most likely due to virus-induced neuronal death and immune-related pathology. The past decade, the notion that neurotropic virus infections cause changes to specific neuronal populations, driving accelerated brain ageing and neurodegeneration has become an emerging concept. However, the interplay between virus infection, inflammation, neuronal death and neurodegeneration remains unravelled. In this project, I propose to investigate virus-induced neuroinflammation and its effect on pathways underlying neurodegeneration with frontline imaging techniques. To do so, I will optimise ex vivo optical projection tomography (OPT) and positron emission tomography (PET) for neuroinflammation and tau tangles and develop accurate image-based quantification pipelines for the proposed markers. These will thereafter be applied to study the neuroinflammatory course in acute flavivirus infection and, to unravel the specific role of the microglia in infection and neuroinflammation. Finally, I will investigate the effect of infection and virus-induced neuroinflammation on induction of neurodegeneration, reflected the induction of tauopathy. Taken together, this project will lead to the development of advanced ex vivo imaging techniques to visualise neuroinflammation and virus-induced neurodegeneration and, will improve our understanding on how neurotropic flaviviruses drive the brain into accelerated ageing, thereby priming neurodegeneration.