Variable susceptibility of intestinal organoid-derived monolayers to SARS-CoV-2 infection.

Gastrointestinal effects associated with Coronavirus Disease 2019 (COVID-19) are highly variable for reasons that are not understood. In this study, we used intestinal organoid-derived cultures differentiated from primary human specimens as a model to examine interindividual variability. Infection of intestinal organoids derived from different donors with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in orders of magnitude differences in virus replication in small intestinal and colonic organoid-derived monolayers. Susceptibility to infection correlated with angiotensin I converting enzyme 2 (ACE2) expression level and was independent of donor demographic or clinical features. ACE2 transcript levels in cell culture matched the amount of ACE2 in primary tissue, indicating that this feature of the intestinal epithelium is retained in the organoids. Longitudinal transcriptomics of organoid-derived monolayers identified a delayed yet robust interferon signature, the magnitude of which corresponded to the degree of SARS-CoV-2 infection. Interestingly, virus with the Omicron variant spike (S) protein infected the organoids with the highest infectivity, suggesting increased tropism of the virus for intestinal tissue. These results suggest that heterogeneity in SARS-CoV-2 replication in intestinal tissues results from differences in ACE2 levels, which may underlie variable patient outcomes.

Déclaration de conflit d'intérêts

I have read the journal’s policy and the authors of this manuscript have the following competing interests: K.C. has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech, and Abbvie. K.C. has consulted for or received an honoraria from Puretech Health, Genentech, and Abbvie. K.C. holds U.S. patent 10,722,600 and provisional patent 62/935,035 and 63/157,225. K.C. is a co-investigator on the Post-Acute Sequelae of SARS-CoV-2 Infection Initiative funded by the NIH (OT2HL161847). J.A. has received research support from BioFire Diagnostics. J.A. reports consultancy fees, honorarium, or advisory board fees from BioFire Diagnostics, Janssen, Abbvie, and Pfizer. J.A. holds U.S. patent 2012/0052124A1.