At Harvard’s Wyss Institute researchers used an intestine-on-a-chip to study the way a coronavirus infects the intestines, and the influence of various drugs and immune cells on this process. The intestine chip revealed that remdesivir, a drug that received FDA emergency use authorization for COVID-19 treatment, actually damaged the intestinal tissue and did not reduce the infection. The microfluidic device allowed the researchers to identify other drugs that could be a better fit for treating coronavirus infection in the intestine.
While the classic respiratory symptoms of COVID-19 receive most attention in the media, as many as 60% of COVID-19 patients will experience gastrointestinal symptoms, such as diarrhea, nausea, and gastrointestinal pain. The intestine is an ideal place for SARS?CoV?2 to infiltrate our cells, as it contains high levels of the ACE2 receptor protein that provides an entry point for the virus.
Studying intestinal SARS?CoV?2 infection is tricky. Animal models are complex and expensive, and do not accurately reflect the situation in humans, whereas cells or organoids in a dish are also limited in their ability to mimic the gut. To address this, a couple years ago the Wyss Institute researchers developed an intestine-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 interior surface. The channels are separated by a permeable membrane, so that substances can permeate from the ‘blood’ to the ‘gut’ and vice versa. To top it off, the device applies a rhythmic stretching force to the cells to mimic the peristaltic motions of the gut.
The Wyss team used the device to study the effects of a coronavirus that uses the ACE2 receptor to enter cells, just like SARS-CoV-2, and studied whether various drugs could reduce infection and the resulting tissue damage. After infection, the epithelial layer became damaged and leaky. Surprisingly, the researchers found that remdesivir, a drug that has received emergency FDA authorization for COVID-19 treatment, actually damaged the intestinal tissue and did not reduce the infection, whereas another drug called Nafamostat, a synthetic serine protease inhibitor that acts as an anti-coagulant, reduced the viral levels in the device.
“This study demonstrates that we can explore complex interactions between cells, pathogens, and drugs in the human intestine using our Intestine Chip as a preclinical model,” said Don Ingber, a researcher involved in the study, via a press release. “We hope it proves useful in the ongoing effort to better understand the effects of SARS-CoV-2 and to identify drugs that could be used to combat future viral pandemics.”
Study in Frontiers in Pharmacology: Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip