US Pharm. 2021;46(12):1.
Most are familiar with COVID-19’s hallmark symptoms of anosmia and difficulty breathing, but 60% of patients infected with SARS-CoV-2 also report gastrointestinal symptoms, such as nausea, diarrhea, and stomach pain.
Infection of the gut, which expresses high levels of the angiotensin-converting enzyme 2 (ACE2) receptor protein that SARS-CoV-2 uses to enter cells, is correlated with more severe cases of COVID-19, but the exact interactions between the virus and intestinal tissue are difficult to study in human patients.
To solve that problem, a team of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and several other organizations in Boston used a human intestine chip previously developed at the Institute to study coronavirus infection and potential treatments. The researchers infected the intestine chip with a coronavirus called NL63 that causes the common cold and, like SARS-CoV-2, uses the ACE2 receptor to enter cells.
Next, they tested the effects of various drugs that have been proposed for treating SARS-CoV-2 infection, finding that a drug called nafamostat reduced infection while the drug remdesivir, which has been used to treat COVID-19 patients, did not reduce infection and actually damaged the intestinal tissue. This new preclinical model is described in Frontiers in Pharmacology.
Having established that their intestine chip could successfully model interactions between viruses, drugs, and the gut, the team tested a variety of other oral drugs, including toremifene, nelfinavir, clofazimine, and fenofibrate, all of which have been shown to inhibit infection by SARS-CoV-2 and other viruses in vitro. Of those, only toremifene showed similar efficacy to nafamostat in reducing NL63 viral load.
Because the immune system interacts with both pathogens and drugs via the inflammatory response, the researchers then introduced a mixture of human immune cells called peripheral blood mononuclear cells (PBMCs) into the blood vessel channel of the intestine chip. They found that more PBMCs attached themselves to the blood vessel wall in chips that had been infected with NL63 than in uninfected chips, and that the blood vessel cells were damaged.
Pretreating the intestine chip with nafamostat prior to the introduction of the virus and PBMCs reduced the secretion of some cytokines, but it did not mitigate the blood vessel damage or suppress the inflammatory response completely. Nafamostat pretreatment did, however, increase the production of an antimicrobial protein called lipocalin-2, implying that this type of protein could play a role in the cellular response to coronavirus infections.
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