Type I and Type III Interferons Differentially Shape Antiviral Defense and Epithelial Integrity at the Choroid Plexus

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 <i>in vivo</i> 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.