Storming the castle: Usutu virus vs. West Nile virus: Insights into neuroinvasion

West Nile virus (WNV) and Usutu virus (USUV) are mosquito-borne viruses that can infect humans. However, WNV leads to thousands of cases severe neurological disease and hundreds of fatalities annually, whereas USUV rarely causes disease and is generally less severe. The research in this thesis aimed to uncover whether the apparent differences in pathogenicity between USUV and WNV stemmed from a difference in their ability to gain access to and infect the brain. Using 3D brain models and 2D neuronal cultures, we found that both viruses could infect and replicate in neurons, but USUV did so less than WNV, suggesting a possible reason for the lower disease severity induced by USUV.

To examine invasion into the brain, we used a model of the blood-brain barrier (BBB) and saw that both viruses could invade across this barrier from the blood into the brain compartment. We studied another route of invasion along motor neurons and saw that WNV could replicate and spread, but USUV could not due to induction of a robust immune response. These findings suggest USUV cannot use an important route of invasion into the brain, which could explain the reduced incidence of disease compared with WNV.

Additionally, the models developed and employed in this thesis could act as platform to assess the neurotropism and neuroinvasive potential of other emerging viruses, aiding in public health preparedness.