Dissecting host/pathogen interactions in the gastrointestinal epithelium.

Abstract

Human intestinal epithelial cells (hIECs) are arranged as a monolayer of cells and provide the first line of defense against invading pathogens. Upon viral infection hIECs upregulate type I and III interferons to control the infection. These interferons lead to the induction of hundreds of interferon stimulated genes (ISGs) that aid in the clearance of the virus and protection of uninfected cells. Upon infection hIECs preferentially upregulate type III interferons to clear the infection. We and others have shown that when added in trans both type I and type III interferons act on hIECs as key antiviral cytokines against several enteric viruses, however they achieve their antiviral results using unique patterns of ISGs. Importantly, while hundreds of ISGs have been described using mainly enterocyte models, whether all cell types in the human gastrointestinal tract upregulate the same ISGs following enteric virus infection has yet to be addressed. Using human intestinal mini-gut organoids, multiplex RNA FISH and single cell RNA sequencing (scRNA-Seq), we have been able to determine the intestinal cell type specific response to virus infection. Our analysis showed that each intestinal cell type in the human gastrointestinal tract upregulated a unique pattern of ISGs to combat enteric virus infection. Further investigations of these ISG expression pattern will help us understand virus tropism and virus clearance mechanisms used by hIECs.