Advances in understanding interferon-mediated immune responses to enteric viruses in intestinal organoids

Abstract

Interferons (IFN) are antiviral cytokines with critical roles in regulating pathogens at epithelial barriers, but their capacity to restrict human enteric viruses has been incompletely characterized in part due to challenges in cultivating some viruses in vitro, particularly human norovirus. Accordingly, advancements in the development of antiviral therapies and vaccine strategies for enteric viral infections have been similarly constrained. Currently emerging is the use of human intestinal enteroids (HIEs) to investigate mechanisms of human enteric viral pathogenesis. HIEs provide a unique opportunity to investigate host-virus interactions using an in vitro system that recapitulates the cellular complexity of the in vivo gastrointestinal epithelium. This approach permits the exploration of intestinal epithelial cell interactions with enteric viruses as well as the innate immune responses mediated by IFNs and IFN-stimulated genes. Here, we describe recent findings related to the production, signaling, and function of IFNs in the response to enteric viral infections, which will ultimately help to reveal important aspects of pathogenesis and facilitate the future development of therapeutics and vaccines.

Keywords: astrovirus; enteric virus; enteroid; interferon; interferon-stimulated genes; norovirus; organoid; rotavirus.

Figure 1

Human intestinal enteroid (HIE) derivation and culture for host-pathogen and disease modeling. HIEs are derived from the intestinal crypts and directly embedded into basement membrane-like matrix (BME) to generate epithelial enteroid cultures with differentiated cell types to model host-virus interactions. Figure created with BioRender.com.

Figure 2

Human intestinal enteroids (HIEs) support the discovery of interferon (IFN) responses to enteric viruses. (A) STAT1 ^-/- HIEs, which lack IFN signaling, demonstrate enhanced norovirus GII.3 replication whereas exogenous type I and III IFN reduce replication of both GII.4 and GII.3 in wild-type HIEs. (B) Human rotavirus (HRV) infection of HIEs induces type III IFNs, while pretreatment of HIEs with exogenous but not endogenous type I and III IFNs can inhibit HRV replication. (C) Treatment with exogenous type I and III IFNs prior to human astrovirus (HAstV) infection reduces viral replication while treatment with ruxolitinib, a JAK1/JAK2 inhibitor, increases HAstV replication. HAstV induces both type I and III IFN responses. (D) Type I or III IFN treatment of HIE monolayers inhibits replication of adenovirus HAdV-41p. Figure created with BioRender.com.