Abstract
Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. To investigate whether USUV is able to infect the brain similarly to WNV and ZIKV, we determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-β and 2’C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers. USUV and ZIKV reached comparable titers and all three viruses primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-β inhibited replication of the arboviruses, while 2’C-methyl-cytidine reduced titers of USUV and ZIKV, but not WNV. Collectively, USUV can infect human brain tissue, showing similarities in replication, tropism and neurovirulence as WNV and ZIKV. Further, this model system can be applied as a preclinical model to determine the efficacy and safety of drugs to treat viral infections of the brain.