Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response

Saygili, Ecem; Yıldız-Ozturk, Ece; Green, Macauley J.; Ghaemmaghami, Amir M.; Yeşil-Çeliktaş, Özlem

doi:10.1063/5.0038924

Cited by 23 publications

(14 citation statements)

References 134 publications

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“…Epithelial infection of the Intestine Chip by introducing NL63 virus into the lumen of the upper channel resulted in a significant but transient increase in virus load, as detected by Reverse Transcriptase-quantitative polymerase Chain Reaction (RT-qPCR) analysis of subgenomic viral RNA transcripts (Figure 2A). While the presence of endothelium was shown to influence influenza virus infection in Lung Airway Chips in past studies (Teijaro et al, 2011;Saygili et al, 2021;Si et al, 2021), the presence of endothelium did not significantly alter infection of intestinal epithelium by NL63 (Supplementary Figure S4). Virus levels were highest 24 h after infection, decreased by 48 h, and returned nearly to baseline levels by 72 h (Figure 2A).…”

Section: Inhibition Of Nl63 Infection By Nafamostat But Not Remdesivirmentioning

confidence: 81%

Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip

Bein¹,

Kim²,

Goyal³

et al. 2021

Front. Pharmacol.

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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.

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Section: Inhibition Of Nl63 Infection By Nafamostat But Not Remdesivirmentioning

confidence: 81%

Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip

Bein¹,

Kim²,

Goyal³

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…2A). While the presence of endothelium was shown to influence influenza virus infection in Lung Airway Chips in past studies 2,20,21 , the presence of endothelium did not significantly alter infection of intestinal epithelium by NL63 (Supp. Fig.…”

Section: Inhibition Of Nl63 Infection By Nafamostat But Not Remdesivirmentioning

confidence: 87%

Enteric coronavirus infection and treatment modeled with an immunocompetent human intestine-on-a-chip

Bein¹,

Kim²,

Goyal³

et al. 2021

Preprint

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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 (PMBCs). 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.

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“…ALI was successfully established on the BoC device, a key feature for epidermal differentiation. This feature is also ideal for establishing other complex models such as lung-on-a-chip since respiratory tract epithelial cells interact with both liquid and air in vivo [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Barrier-on-a-Chip with a Modular Architecture and Integrated Sensors for Real-Time Measurement of Biological Barrier Function

2021

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Biological barriers are essential for the maintenance of organ homeostasis and their dysfunction is responsible for many prevalent diseases. Advanced in vitro models of biological barriers have been developed through the combination of 3D cell culture techniques and organ-on-chip (OoC) technology. However, real-time monitoring of tissue function inside the OoC devices has been challenging, with most approaches relying on off-chip analysis and imaging techniques. In this study, we designed and fabricated a low-cost barrier-on-chip (BoC) device with integrated electrodes for the development and real-time monitoring of biological barriers. The integrated electrodes were used to measure transepithelial electrical resistance (TEER) during tissue culture, thereby quantitatively evaluating tissue barrier function. A finite element analysis was performed to study the sensitivity of the integrated electrodes and to compare them with conventional systems. As proof-of-concept, a full-thickness human skin model (FTSm) was grown on the developed BoC, and TEER was measured on-chip during the culture. After 14 days of culture, the barrier tissue was challenged with a benchmark irritant and its impact was evaluated on-chip through TEER measurements. The developed BoC with an integrated sensing capability represents a promising tool for real-time assessment of barrier function in the context of drug testing and disease modelling.

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Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response

Cited by 23 publications

References 134 publications

Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip

Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip

Enteric coronavirus infection and treatment modeled with an immunocompetent human intestine-on-a-chip

Barrier-on-a-Chip with a Modular Architecture and Integrated Sensors for Real-Time Measurement of Biological Barrier Function

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