Neuronal interactions in forebrain organoids lead to protective antiviral responses

Abstract

Neurotropic viruses are the most common cause of infectious encephalitis and largely target neurons for infection. Our understanding of intrinsic neuronal innate immune response capacity to mediate protective antiviral responses remains incomplete. Here, we evaluated the role of intercellular crosstalk in mediating intrinsic neuronal immunity and its contribution to limiting viral infection. We found that in the absence of viral antagonism, neurons transcriptionally induce robust interferon signaling and can effectively signal to neighboring uninfected bystander neurons. Yet, in two-dimensional cultures, this dynamic response did not restrict viral spread. Interestingly, this differed in the context of viral infection in three-dimensional forebrain organoids with complex neuronal interactions, where we observed protective capacity. We show antiviral crosstalk between infected neurons and bystander neural progenitors is mediated by type I interferon signaling. Using spatial transcriptomics, we then uncover distinct regions of bystander progenitor interactions that reveal critical underpinnings of protective antiviral responses, including expression of distinct antiviral genes. These findings underscore the importance of intercellular communication in protective antiviral immunity in the brain and implicate key contributions to protective antiviral signaling.