Single cell approach to study host/enteric virus interaction in human mini-gut organoids

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Characterization of host/enteric pathogens interactions using immortalized intestinal epithelial cell lines do not reflect the complex environment that both the pathogens and the cellular intrinsic immune system face in the human gut. Indeed, the intestinal tract is characterized by the presence of multiple specific cell lineages arranged within a crypt/villi axis, which must tolerate the commensal flora but be primed for enteric virus attacks. In this proposal, we will exploit both single cell transcriptomic analyses and visualization of immune response in live mini-gut organoids during enteric virus infection. We will characterize the intrinsic innate immune response of intestinal epithelial cells in the context of the intestinal epithelium organization. This will allow us to describe, at the single cell level, the antiviral innate immune response generated by each individual cell type naturally present in the human gut and to characterize how both infection and immune response spread in space and time within the crypt/villi axis organized gut epithelium. At the completion of this project we will have developed a physiological culture system allowing us to address the complex interplay between pathogen/epithelial cells. This will offer us unprecedented perspectives to study host/pathogen interactions and intestinal disease.