Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip
Name
fphar-12-718484.pdf
Description
Published version
Size
1.48 MB
Format
Adobe PDF
Checksum (MD5)
2837f2de428b4706753726ac0b248b80
Author(s)
Bein, Amir
Kim, Seongmin
Goyal, Girija
Cao, Wuji
Fadel, Cicely
Naziripour, Arash
Sharma, Sanjay
Swenor, Ben
LoGrande, Nina
Nurani, Atiq
Date Issued
2021
Journal
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Citation
Bein, Amir, Kim, Seongmin, Goyal, Girija, Cao, Wuji, Fadel, Cicely et al. 2021. "Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip." Frontiers in Pharmacology, 12.
Version
Final published version
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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Ragon Institute of MGH, MIT and Harvard
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.3389/FPHAR.2021.718484
