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.

Reverse Genetics of Murine Rotavirus: A Comparative Analysis of the Wild-Type and Cell-Culture-Adapted Murine Rotavirus VP4 in Replication and Virulence in Neonatal Mice

“…It would also be of interest to test these viruses in an adult mouse model to see if different results are obtained to those in the neonatal mouse system. Finally, although human enteroid cultures have proven a great tool for modeling primary human intestinal epithelial cells and for studying RV infection [40][41][42], such a system is lacking for the murine enteroids, which would be useful for teasing apart the stage of entry affected by VP8* and/or VP5* mutations. In conclusion, we have developed a reverse genetics for murine RV.…”

Candida albicans-enteric viral interactions—The prostaglandin E2 connection and host immune responses

“…The use of human intestinal enteroids (HIEs) will provide a better opportunity for studying these interactions in the future as HIEs epitomize the nuances involved in in vivo gastrointestinal epithelium. 256 The COX2/PGE 2 pathway can be a therapeutic target for regulating viral infections and understanding viral dependence on PGE 2 during co-infections.…”

“…Lastly, research on the key role of interferon (IFN) signaling in inhibiting viral pathogenesis and proliferation at mucosal sites has increased knowledge of host-viral interactions, especially in murine models. The major enteric viruses discussed here are reported to induce type I, type II, and type III IFNs, although certain aspects remain understudied due to limitations in culturing techniques, especially for viruses such as human noroviruses (Nolan and Baldridge, 256 review the use of human organoids in overcoming these limitations). Compared to type I and III, type II IFNs are well studied for controlling bacterial and fungal infections but are less characterized in the context of viral infections.…”

Glycochenodeoxycholic acid and ceramide suppress the antiviral effect of 25-hydroxycholesterol against human norovirus infection in human intestinal enteroids

“…HIE are primary cells derived from intestinal biopsies, maintained in a 3D culture, and seeded as monolayers to support human norovirus replication (10,11). This novel cell culture system has revolutionized the norovirus field and enhanced our ability to study norovirus infection, assess efficacy of control measures, and measure adaptive and innate immune responses (12)(13)(14).…”