Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response

Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to coronavirus disease 2019 (COVID-19) usually results in respiratory disease, but extrapulmonary manifestations are of major clinical interest. Intestinal symptoms of COVID-19 are present in a significant number of patients, and include nausea, diarrhea, and viral RNA shedding in feces. Human induced pluripotent stem cell-derived intestinal organoids (HIOs) represent an inexhaustible cellular resource that could serve as a valuable tool to study SARS-CoV-2 as well as other enteric viruses that infect the intestinal epithelium. Here, we report that SARS-CoV-2 productively infects both proximally and distally patterned HIOs, leading to the release of infectious viral particles while stimulating a robust transcriptomic response, including a significant upregulation of interferon-related genes that appeared to be conserved across multiple epithelial cell types. These findings illuminate a potential inflammatory epithelial-specific signature that may contribute to both the multisystemic nature of COVID-19 as well as its highly variable clinical presentation.
Highlights • Human iPSC-derived intestinal organoids are susceptible to productive SARS-CoV-2 infection • SARS-CoV-2 infection is accompanied by ultrastructural changes in HIO morphology • RNA-seq revealed a common inflammatory signature across multiple epithelial cell types • HIOs are a viable tool to model host response to infectious pathogens in the GI tract
In this article, Gustavo Mostoslavsky, Elke Mühlberger, and colleagues model the host response to intestinal SARS-CoV-2 infection using iPSC-derived regionally patterned intestinal organoids. Specifically, they highlight productive infection of mesenchyme-free intestinal and colonic organoids and demonstrate that they recapitulate intrinsic inflammatory transcriptomic responses to infection that have been shown in other epithelial cell types.