Enterovirus Replication and Dissemination Are Differentially Controlled by Type I and III Interferons in the Gastrointestinal Tract

Enteroviruses are among the most common viral infectious agents of humans and cause a broad spectrum of mild-to-severe illness. Enteroviruses are transmitted primarily by the fecal-oral route, but the events associated with their intestinal replication in vivo are poorly defined. Here, we developed a neonatal mouse model of enterovirus infection by the enteral route using echovirus 5 and used this model to define the differential roles of type I and III interferons (IFNs) in enterovirus replication in the intestinal epithelium and subsequent dissemination to secondary tissues. We show that human neonatal Fc receptor (FcRn), the primary receptor for echoviruses, is essential for intestinal infection by the enteral route and that type I IFNs control dissemination to secondary sites, including the liver. In contrast, type III IFNs limit echovirus infection in the intestinal epithelium, and mice lacking this pathway exhibit extended epithelial replication. Finally, we show that echovirus infection in the small intestine is cell type specific and occurs exclusively in enterocytes. These studies define the type-specific roles of IFNs in enterovirus infection of the gastrointestinal (GI) tract and the cellular tropism of echovirus replication in the intestinal epithelium.