Frontiers in Pharmacology (Oct 2021)
Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip
- Amir Bein,
- Seongmin Kim,
- Girija Goyal,
- Wuji Cao,
- Cicely Fadel,
- Arash Naziripour,
- Sanjay Sharma,
- Ben Swenor,
- Nina LoGrande,
- Atiq Nurani,
- Vincent N. Miao,
- Vincent N. Miao,
- Vincent N. Miao,
- Vincent N. Miao,
- Andrew W. Navia,
- Andrew W. Navia,
- Andrew W. Navia,
- Carly G. K. Ziegler,
- Carly G. K. Ziegler,
- Carly G. K. Ziegler,
- Carly G. K. Ziegler,
- Carly G. K. Ziegler,
- José Ordovas Montañes,
- José Ordovas Montañes,
- José Ordovas Montañes,
- Pranav Prabhala,
- Min Sun Kim,
- Rachelle Prantil-Baun,
- Melissa Rodas,
- Amanda Jiang,
- Lucy O’Sullivan,
- Gladness Tillya,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Donald E. Ingber,
- Donald E. Ingber,
- Donald E. Ingber
Affiliations
- Amir Bein
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Seongmin Kim
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Girija Goyal
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Wuji Cao
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Cicely Fadel
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Arash Naziripour
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Sanjay Sharma
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Ben Swenor
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Nina LoGrande
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Atiq Nurani
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Vincent N. Miao
- Program in Health Sciences & Technology, Harvard Medical School & MIT, Cambridge, MA, United States
- Vincent N. Miao
- Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Cambridge, MA, United States
- Vincent N. Miao
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Vincent N. Miao
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States
- Andrew W. Navia
- Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Cambridge, MA, United States
- Andrew W. Navia
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Andrew W. Navia
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States
- Carly G. K. Ziegler
- Program in Health Sciences & Technology, Harvard Medical School & MIT, Cambridge, MA, United States
- Carly G. K. Ziegler
- Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Cambridge, MA, United States
- Carly G. K. Ziegler
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Carly G. K. Ziegler
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States
- Carly G. K. Ziegler
- Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, United States
- José Ordovas Montañes
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- José Ordovas Montañes
- Harvard Stem Cell Institute, Cambridge, MA, United States
- José Ordovas Montañes
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA, United States
- Pranav Prabhala
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Min Sun Kim
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Rachelle Prantil-Baun
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Melissa Rodas
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Amanda Jiang
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Lucy O’Sullivan
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Gladness Tillya
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Alex K. Shalek
- Program in Health Sciences & Technology, Harvard Medical School & MIT, Cambridge, MA, United States
- Alex K. Shalek
- Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Cambridge, MA, United States
- Alex K. Shalek
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Alex K. Shalek
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States
- Donald E. Ingber
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Donald E. Ingber
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States
- Donald E. Ingber
- 0Vascular Biology Program and Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA, United States
- DOI
- https://doi.org/10.3389/fphar.2021.718484
- Journal volume & issue
-
Vol. 12
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.
Keywords
