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Updated: Oct 13, 2025
Author Spotlight: Developing Immunocompetent Organ-on-Chip Models for Infectious Disease Research
Published on: May 24, 2024
Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip
Amir Bein1, Seongmin Kim1, Girija Goyal1
1Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States.
Abstract:
Many patients infected with coronaviruses, such as SARS-CoV-2 and NL63 that use ACE2 receptors to infect cells, exhibit gastrointestinal symptoms and viral proteins are found in the human gastrointestinal tract, yet little is known about the inflammatory and pathological effects of coronavirus infection on the human intestine. Here, we used a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by patient organoid-derived intestinal epithelium interfaced with human vascular endothelium to study host cellular and inflammatory responses to infection with NL63 coronavirus. These organoid-derived intestinal epithelial cells dramatically increased their ACE2 protein levels when cultured under flow in the presence of peristalsis-like mechanical deformations in the Intestine Chips compared to when cultured statically as organoids or in Transwell inserts. Infection of the intestinal epithelium with NL63 on-chip led to inflammation of the endothelium as demonstrated by loss of barrier function, increased cytokine production, and recruitment of circulating peripheral blood mononuclear cells (PBMCs). Treatment of NL63 infected chips with the approved protease inhibitor drug, nafamostat, inhibited viral entry and resulted in a reduction in both viral load and cytokine secretion, whereas remdesivir, one of the few drugs approved for COVID19 patients, was not found to be effective and it also was toxic to the endothelium. This model of intestinal infection was also used to test the effects of other drugs that have been proposed for potential repurposing against SARS-CoV-2. Taken together, these data suggest that the human Intestine Chip might be useful as a human preclinical model for studying coronavirus related pathology as well as for testing of potential anti-viral or anti-inflammatory therapeutics.
Insights
A human intestine-on-a-chip model revealed coronavirus (NL63) infection causes intestinal inflammation. Nafamostat effectively reduced viral entry and inflammation, while remdesivir showed toxicity and limited efficacy in this preclinical model.
Area of Science:
- Gastroenterology
- Virology
- Organ-on-a-chip technology
Background:
- Coronaviruses, including SARS-CoV-2, frequently cause gastrointestinal symptoms.
- The pathological effects of coronavirus infection on the human intestine are not well understood.
- ACE2 receptors are key entry points for some coronaviruses into host cells.
Purpose of the Study:
- To investigate the inflammatory and pathological effects of NL63 coronavirus infection on the human intestine.
- To establish and utilize a human intestine-on-a-chip model for studying coronavirus-intestinal interactions.
- To evaluate potential therapeutic interventions for coronavirus-induced intestinal pathology.
Main Methods:
- Utilized a human intestine-on-a-chip microfluidic device lined with patient organoid-derived intestinal epithelium and human vascular endothelium.
- Cultured intestinal epithelial cells under flow with mechanical deformations to increase ACE2 expression.
- Infected the on-chip intestinal epithelium with NL63 coronavirus and assessed inflammatory responses and endothelial barrier function.
- Tested the efficacy of nafamostat and remdesivir as potential therapeutics.
Main Results:
- Intestine-on-a-chip model demonstrated increased ACE2 expression in intestinal epithelial cells under dynamic culture conditions.
- NL63 infection induced endothelial inflammation, characterized by barrier dysfunction, elevated cytokines, and immune cell recruitment.
- Nafamostat inhibited NL63 viral entry, reduced viral load, and decreased cytokine secretion.
- Remdesivir was ineffective and exhibited toxicity to the endothelium.
Conclusions:
- The human intestine-on-a-chip serves as a valuable preclinical model for studying coronavirus-induced intestinal pathology.
- Nafamostat shows promise as a therapeutic agent for managing coronavirus-related gastrointestinal complications.
- This model facilitates the testing of antiviral and anti-inflammatory drugs for potential repurposing against SARS-CoV-2.
