Human organoids provide new insights into early stage enterovirus infection

Enteroviruses, transmitted by fecal-oral route, are associated with several human diseases, which have a wide range of severity. In many cases infections can be asymptomatic, however some can result in severe conditions such as meningitis, encephalitis, myocarditis or even death.

The early stages of the disease are crucial as this is when the virus crosses the small intestinal (SI) epithelium to secondary sites of infection resulting in the more severe pathologies. Existing models have not represented the complexity of the SI tissue, such as the use of cell lines, or had to bypass the GI tract and therefore represent later stages of infection, such as within mouse models.

The recent publication reviewed in this spotlight utilized human fetal SI organoids to study infection of three different enteroviruses: coxsackievirus B (CVB), echovirus 11 (E11) and EV71, all of which replicated within the organoids. E11 infection resulted in cell death, which was suggested to be via necrosis and associated with mislocalization of occludin.

Comparison of Caco-2 cells and organoids via RNA-seq showed that their transcriptional profiles were distinct, and in particular the secretory lineages were enriched in organoids. Lower infection efficiencies were observed in the organoids for all viruses in comparison to Caco-2 cells.

Unlike the Caco-2 cell line, infection with E11 induced anti-viral and inflammatory signals from organoids. However, these inductions were not observed due to EV17 or CVB infections, suggesting a viral-specific response.

The authors sought to determine whether the E11 virus targeted specific cell types, something they could not do in Caco-2 cells. They observed a lack of infection in goblet cells, even when the percentage of these cells was increased via the induction of secretory cell differentiation. However, they did see an association between enteroendocrine cells and viral infection.

Previous findings led to speculation that enteroviruses crossed the SI via non‑infectious transcytosis across M cells. However, this study shows the viruses can infect SI tissues and could have a profound effect on enterovirus pathology. The study also highlights the advantages that 3D intestinal models provide over transformed cell lines.

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Epistem's Organoid Models

Epistem have presented developmental work within the organoid model in the areas of epithelial regeneration and GI toxicity at various conferences.

Potential readouts in this model could be proliferation, differentiation, apoptosis, cytotoxicity screening and protein and gene expression.

Drummond, C. et al. (2016). “Enteroviruses Infect Human Enteriods and Induce Antiviral Signaling in a Cell Lineage‑Specific Manner.” PNAS.

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