Type III interferon signaling restricts Enterovirus 71 infection of goblet cells

Recent worldwide outbreaks of enterovirus (EV71) have caused major epidemics of hand, foot, and mouth disease (HFMD) with severe neurological complications, including acute flaccid paralysis. EV71 is transmitted by the enteral route, but very little is known about the mechanisms it utilizes to cross the human gastrointestinal (GI) tract. Using primary human intestinal epithelial monolayers, we show that EV71 infects the GI epithelium from the apical surface, where it preferentially infects goblet cells. Unlike echovirus 11 (E11), an enterovirus that infects enterocytes, EV71 infection did not alter epithelial barrier function, but did reduce the expression of a goblet cell-derived mucin, suggesting it alters goblet cell function. We also show that the intestinal epithelium responds to EV71 infection through the selective induction of type III IFNs, which potently restrict EV71 replication. Collectively, these findings define the early events associated with EV71 infections of the human intestinal epithelium and show that host IFN signaling controls replication in an IFN-specific manner.