Enterovirus replication and dissemination are differentially controlled by type I and III interferons in the GI tract

Abstract

Enteroviruses are amongst the most common viral infectious agents of humans and cause a broad spectrum of mild-to-severe illness. Enteroviruses are primarily transmitted 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 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 enterovirus infection in the intestinal epithelium and mice lacking this pathway exhibit persistent 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 GI tract and the cellular tropism of echovirus intestinal replication.

An in vivo model of echovirus-induced meningitis in neonates

“…hFcRn Tg32 mice are deficient in expression of mouse FcRn and express human FcRn under the control of the native human promotor (29). To determine if type III IFNs also play a role in echovirus infections at secondary sites of infection including the brain, we generated hFcRn Tg32 mice deficient in IFNLR expression, the receptor for type III IFNs (hFcRn Tg32 -IFNLR -/- ) (30). We used six genotypes of mice, including the hFcRn mice described above (hFcRn Tg32 , hFcRn Tg32 -IFNAR -/- , and hFcRn Tg32 -IFNLR -/- ) and animals expressing murine FcRn that were immunocompetent (C57/BL6, WT) or deficient in type I or III IFN signaling (IFNAR -/- or IFNLR -/- , respectively) ( Figure 1A ).…”

“…However, because we used brain tissue homogenates and human studies can are restricted to CSF, it is unclear which cytokines induced by echovirus infections mediate the influx of immune cells observed in echovirus-induced meningitis. Although the differential roles of type I and III IFNs has been established in the respiratory and intestinal epithelium during enterovirus infection (30,(38)(39)(40), whether these IFNs play distinct roles in enterovirus-induced meningitis has remained unclear. Our data suggest that type I IFNs are the sole barrier to echovirus infection of the CNS, which is consistent with previous work defining indicating that these IFNs form at least one bottleneck to poliovirus access to the CNS (41).…”

“…no. 014565) mice with B6.Ifnlr -/- /J mice (30). Breeders were established that were deficient in mouse FcRn and IFNLR and were homozygous for the hFcRn transgene.…”