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. IMPORTANCE Echovirus infections are associated with a broad spectrum of illness, particularly in neonates, and are primarily transmitted through the fecal-oral route. Little is known regarding how echoviruses infect the gastrointestinal tract and how the intestinal epithelium controls echoviral replication. Here, we establish an in vivo mouse model of echovirus infection by the enteral route and define the differential roles of type I and III interferons (IFNs) in controlling viral replication in the intestine. These findings provide important insights into the mechanisms by which echoviruses infect the GI tract and the epithelium-specific antiviral pathways that control this infection. Echovirus infections are associated with a broad spectrum of illness, particularly in neonates, and are primarily transmitted through the fecal-oral route. Little is known regarding how echoviruses infect the gastrointestinal tract and how the intestinal epithelium controls echoviral replication.