Chip for the investigation of intestinal coronavirus infection

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Researchers at the Wyss Institute at Harvard used a gut on a chip to study how a coronavirus infects the intestines and the influence of various drugs and immune cells on this process. The intestinal chip revealed that remdesivir, a drug that received FDA emergency use authorization for the treatment of COVID-19, actually damaged intestinal tissue and did not reduce infection. The microfluidic device allowed researchers to identify other drugs that might be more appropriate to treat coronavirus infection in the gut.

Infecting the intestinal chip with NL63 (central column) caused many changes in tissue, including connections between cells (upper row), the amount of apoptosis (cell death) that occurred (middle row, in red) and the connection of immune cells. to the lining of blood vessels. Treatment with the anticoagulant drug nafamostat (right column) helped combat these interruptions. Credit: Wyss Institute at Harvard University

While classic COVID-19 respiratory symptoms receive more media attention, up to 60% of patients with COVID-19 will experience gastrointestinal symptoms, such as diarrhea, nausea, and gastrointestinal pain. The gut is an ideal place for SARS-CoV-2 to infiltrate our cells, as it contains high levels of the ACE2 receptor protein that provides a point of entry into the virus.

Studying intestinal SARS-CoV-2 infection is complicated. Animal models are complex and expensive and do not accurately reflect the situation of humans, while the cells or organoids in a dish also have a limited ability to mimic the gut. To address this, a couple of years ago Researchers at the Wyss Institute developed a gut on a chip which consists of a device the size of a USB stick that contains two channels lined with cells.

One channel is lined with endothelial cells and the other has intestinal cells on its inner surface. The channels are separated by a permeable membrane, so substances can be impregnated from the “blood” into the “gut” and vice versa. Finally, the device applies a rhythmic stretching force to the cells to mimic the peristaltic movements of the bowel.

The Wyss team used the device to study the effects of a coronavirus that uses the ACE2 receptor to enter cells, like SARS-CoV-2, and studied whether various drugs could reduce infection and the resulting tissue damage. After infection, the epithelial layer was damaged and leaked. Surprisingly, the researchers found that remdesivir, a drug that has received emergency authorization from the FDA for the treatment of COVID-19, actually damaged intestinal tissue and did not reduce infection, while another drug called Nafamostat, a synthetic serine protease inhibitor that acts as an anti-coagulant, reduced viral levels in the device.

“This study demonstrates that we can explore complex interactions between cells, pathogens, and drugs in the human gut using our gut chip as a preclinical model,” said Don Ingber, a researcher involved in the study, through a press release. “We hope it will be useful in the ongoing effort to better understand the effects of SARS-CoV-2 and identify drugs that could be used to combat future viral pandemics.”

Study a Frontiers in pharmacology: Enteric coronavirus infection and treatment modeled with an immunocompetent human gut on a chip

Flashbacks: Intestine chip to study human-microbiome interactions; The chipped bowel technique opens the door to personalized medicine

Via: Harvard Wyss Institute





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