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

The choroid plexus (ChP) forms the blood-cerebrospinal fluid (CSF) barrier, yet how this CNS interface responds to viral infection remains poorly understood. Here, we identify the ChP epithelium as a major target of echovirus infection and establish complementary human organoid and mouse models to define antiviral responses at this barrier. Single-cell RNA sequencing of cerebral organoids revealed preferential infection of ChP epithelial cells, and ChP organoids supported productive infection accompanied by a robust type III interferon (IFN) response. In mice expressing human FcRn, the echovirus receptor, infection similarly targeted the ChP, enabling genetic dissection of IFN signaling in vivo. Type I IFN signaling restricted viral replication and protected against lethal disease. In contrast, type III IFN signaling was dispensable for viral control but promoted ChP epithelial injury and, following viral clearance, was associated with persistent motor deficits, ependymal loss, and ventriculomegaly. These findings reveal distinct functions for type I and III IFNs at the blood-CSF barrier and identify type III IFN signaling as a driver of tissue injury and lasting neurological sequelae following viral infection.