Abstract
The choroid plexus (ChP) forms the primary barrier between the bloodstream and the cerebrospinal fluid (CSF) and serves as a critical neuroimmune interface, yet how it responds to viral infection remains poorly understood. Here, we establish complementary human and mouse platforms to interrogate viral infection at the blood-CSF barrier using echoviruses as a clinically relevant neurotropic model. In human ChP organoids, echovirus infection elicits a robust epithelial type III interferon (IFN-λ) response. In parallel, we develop an in vivo mouse model in which echovirus infection selectively targets the ChP, enabling mechanistic analysis of interferon signaling at this interface. We find that type I and type III interferons play divergent roles during infection: type I IFN signaling is essential for restricting viral replication, whereas type III IFN signaling impairs epithelial repair, exacerbates barrier injury, and worsens long-term structural damage. Together, these findings reveal opposing roles for type I and type III interferons in antiviral defense and tissue repair at the blood-CSF barrier, redefining interferon function at a critical CNS epithelial interface.