Virus-induced apoptosis in human cerebral organoids occurs primarily in committed neurons and is associated with a limited interferon stimulated gene response

La Crosse virus (LACV) is the leading cause of pediatric arboviral encephalitis in the USA. Although the hallmarks of disease are infection and apoptosis of neurons, there is limited knowledge of neuronal responses to virus infection at differing neurodevelopmental stages. Here, we infected induced pluripotent stem-cell (iPSC)-derived human cerebral organoids (COs) containing actively maturing populations of neuronal-lineage cells to examine this process. LACV readily infected COs and caused reduced cell viability. Although neural progenitors and committed neurons were similarly infected, significantly more committed neurons underwent apoptosis. Committed neurons expressed fewer interferon (IFN)-inducible transcripts in response to infection compared to neural progenitors, suggesting a poor anti-viral response. Treatment of infected COs with recombinant IFNs enhanced cell viability, demonstrating a therapeutic potential. This study demonstrates that LACV differentially induces apoptosis in neuronal-lineage cells depending on their stage of maturation and provides analysis for why these cells differ in their responses. Overall design: 2 samples derived from human cerebral organoids were processed using 10x Genomics single cell instrument