Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip
<jats:p>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 cor...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media SA
2022
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| Online Access: | https://hdl.handle.net/1721.1/141283 |
| _version_ | 1826207846720602112 |
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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 GK 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 |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology 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 GK 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 | MIT |
| description | <jats:p>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.</jats:p> |
| first_indexed | 2024-09-23T13:55:53Z |
| format | Article |
| id | mit-1721.1/141283 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:55:53Z |
| publishDate | 2022 |
| publisher | Frontiers Media SA |
| record_format | dspace |
| spelling | mit-1721.1/1412832023-06-20T17:03:31Z 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 GK 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 Harvard University--MIT Division of Health Sciences and Technology Ragon Institute of MGH, MIT and Harvard <jats:p>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.</jats:p> 2022-03-18T14:19:09Z 2022-03-18T14:19:09Z 2021 2022-03-18T14:16:13Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/141283 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. en 10.3389/FPHAR.2021.718484 Frontiers in Pharmacology Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Frontiers Media SA Frontiers |
| spellingShingle | 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 GK 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 |
| url | https://hdl.handle.net/1721.1/141283 |
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