SARS-CoV-2 productively infects human gut enterocytes

Abstract

<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.</jats:p>

SARS-CoV-2 infection and replication in human fetal and pediatric gastric organoids

“…RP-GO of late fetal and pediatric age infected with SARS-CoV-2 shared a transcriptional footprint surprisingly similar to those described for infected human small intestine enteroids 16,17 in which type I IFN genes were either poorly expressed or undetectable, despite enterocytes and gastric cells displaying moderate levels of ISGs primarily involved in the recognition of viral RNA. Moreover, our transcriptional data are in considerable agreement with clinical and experimental profiles derived from COVID-19 patients, infected normal human bronchial epithelial cells and in vivo studies in ferrets 35 that highlighted a negligible expression of genes of the IFN family but a robust expression of chemokines and ISGs.…”

“…Nonetheless, variation in the protein-to-mRNA ratio across organoids of different developmental stage should be taken into account and receptivity investigated in future work. Immunofluorescence staining for the nucleocapsid indicated a clear cytosolic localization of this protein that in some cells was associated with the presence of the cleaved caspase 3, confirming the occurrence of apoptosis in the GI compartment 16 . Apoptosis in infected GI mucosal cells might account at least in part for the frequent abdominal pain, vomit and diarrhea described in COVID-19 patients 32 , in particular in pediatric populations.…”

“…Organoids have attracted great attention, enabling in vitro disease modeling and providing an ideal tool for studying infectious pathogens, particularly of the GI tract 15 . Recent studies have demonstrated how SARS-CoV-2 can efficiently infect human intestinal enteroids 16,17 , providing evidence in support of the hypothesis that sees SARS-CoV-2 as a fecaloral transmissible pathogen. However, it remains to be elucidated whether access to the duodenum depends on passive transport of infected oral fluids across the stomach, or on active viral replication in the gastric mucosa.…”

“…Two recent studies show that the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes and that intestinal organoids derived from the small intestine can be easily infected by SARS-CoV-2 16,17 . Interestingly, intestinal organoids derived from both human and horseshoe bats are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication.…”

“…Other studies showed disruption of 3D organoid organization in favor of a 2D monolayer culture to overcome inner polarity problems in H. pylori infection 31 . Recently, in SARS-CoV-2 infection studies, intestinal organoid 3D structures were sheared to expose the apical viral receptors and then reaggregated in ECM hydrogel droplets 16,17 . In these studies, infection of organoids upon shearing and embedding was attained, as proved by the immunofluorescent staining of viral antigens and detection of viral RNA.…”