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Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip
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 infec...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573067/ https://www.ncbi.nlm.nih.gov/pubmed/34759819 http://dx.doi.org/10.3389/fphar.2021.718484 |
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author | Bein, Amir Kim, Seongmin Goyal, Girija Cao, Wuji Fadel, Cicely Naziripour, Arash Sharma, Sanjay Swenor, Ben LoGrande, Nina Nurani, Atiq Miao, Vincent N. Navia, Andrew W. Ziegler, Carly G. K. Montañes, José Ordovas Prabhala, Pranav Kim, Min Sun Prantil-Baun, Rachelle Rodas, Melissa Jiang, Amanda O’Sullivan, Lucy Tillya, Gladness Shalek, Alex K. Ingber, Donald E. |
author_facet | Bein, Amir Kim, Seongmin Goyal, Girija Cao, Wuji Fadel, Cicely Naziripour, Arash Sharma, Sanjay Swenor, Ben LoGrande, Nina Nurani, Atiq Miao, Vincent N. Navia, Andrew W. Ziegler, Carly G. K. Montañes, José Ordovas Prabhala, Pranav Kim, Min Sun Prantil-Baun, Rachelle Rodas, Melissa Jiang, Amanda O’Sullivan, Lucy Tillya, Gladness Shalek, Alex K. Ingber, Donald E. |
author_sort | Bein, Amir |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8573067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85730672021-11-09 Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip Bein, Amir Kim, Seongmin Goyal, Girija Cao, Wuji Fadel, Cicely Naziripour, Arash Sharma, Sanjay Swenor, Ben LoGrande, Nina Nurani, Atiq Miao, Vincent N. Navia, Andrew W. Ziegler, Carly G. K. Montañes, José Ordovas Prabhala, Pranav Kim, Min Sun Prantil-Baun, Rachelle Rodas, Melissa Jiang, Amanda O’Sullivan, Lucy Tillya, Gladness Shalek, Alex K. Ingber, Donald E. Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2021-10-25 /pmc/articles/PMC8573067/ /pubmed/34759819 http://dx.doi.org/10.3389/fphar.2021.718484 Text en Copyright © 2021 Bein, Kim, Goyal, Cao, Fadel, Naziripour, Sharma, Swenor, LoGrande, Nurani, Miao, Navia, Ziegler, Montañes, Prabhala, Kim, Prantil-Baun, Rodas, Jiang, O’Sullivan, Tillya, Shalek and Ingber. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Bein, Amir Kim, Seongmin Goyal, Girija Cao, Wuji Fadel, Cicely Naziripour, Arash Sharma, Sanjay Swenor, Ben LoGrande, Nina Nurani, Atiq Miao, Vincent N. Navia, Andrew W. Ziegler, Carly G. K. Montañes, José Ordovas Prabhala, Pranav Kim, Min Sun Prantil-Baun, Rachelle Rodas, Melissa Jiang, Amanda O’Sullivan, Lucy Tillya, Gladness Shalek, Alex K. Ingber, Donald E. Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip |
title | Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip |
title_full | Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip |
title_fullStr | Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip |
title_full_unstemmed | Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip |
title_short | Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip |
title_sort | enteric coronavirus infection and treatment modeled with an immunocompetent human intestine-on-a-chip |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573067/ https://www.ncbi.nlm.nih.gov/pubmed/34759819 http://dx.doi.org/10.3389/fphar.2021.718484 |
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