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The longer the corona pandemic lasts, the more scientists learn about the virus. And these research findings are anything but reassuring. Whereas in the beginning it was said that SARS-CoV-2 is a pulmonary virus and COVID-19 is a pulmonary infection, this now seems to be changing from one week to the next.

Observations in patients are revealing more and more that this novel coronavirus can cause more lasting harm to the body than previously assumed. Besides damage to heart muscles, it can also impair blood clotting. This, in turn, can eventuate in thromboses and embolisms. Plus, nerves may be attacked as well. Researchers at the Hubrecht Institute in Utrecht, the Erasmus MC University in Rotterdam, and the Maastricht University (all in the Netherlands) have now been able to show that the SARS-CoV-2 coronavirus can also infect intestinal cells and can even reproduce in the gut.

New cell culture model

In order to do this, the scientists used state-of-the-art cell culture models of the human intestine to propagate the virus in vitro. They then monitored the reaction of the cells. Their observations of this new cell culture model revealed why around one-third of COVID-19 patients also experience gastrointestinal symptoms such as diarrhea along with the known symptoms such as coughing, sneezing, shortness of breath, and fever. And why the virus can often be detected in stool samples. This fact alone suggests that the virus is capable of spreading via what’s referred to as “fecal-oral transmission.

Coronavirus SARS-CoV-2 (dark circles) on the edge of an intestinal cell (lower left corner). © Kèvin Knoops, Copyright Maastricht University

Even though respiratory and gastrointestinal organs may seem very different, there are some significant similarities. Notably, they both have ACE2 receptors. These are receptors which the SARS-CoV-2 virus that causes COVID-19 uses to penetrate cells. These ACE2 receptors are present in large numbers inside the intestine. However, it was not known until now whether intestinal cells can actually become infected and reproduce virus particles.

Research carried out at home

To answer this question, the Dutch researchers used human intestinal organoids. As in tiny versions of the human intestine that can be cultivated in a laboratory. “These organoids contain the cells of the human intestinal lining. This makes them a compelling model to investigate infection by SARS-CoV-2,” explains Hans Clevers from the Hubrecht Institute.

The scientists used RNA sequencing. A method that’s used to examine which genes are active in the cells for studying the reaction of the intestinal cells to the virus. This approach has shown that so-called interferon-stimulated genes become activated. “These genes are known to fight viral infections. Future research will focus more closely on these genes. And how they might be used to develop new treatments,” the researchers explain.

The organoids were also cultivated under a variety of conditions. That led to cells with higher and lower concentrations of the ACE2 receptor via which SARS-CoV-2 was able to enter the cells. As was stated in the study recently published in the academic journal Science. The researchers found “to their surprise” that the virus-infected cells contained both high and low concentrations of the ACE2 receptor. Ultimately, these studies could lead to new ways of blocking the virus from penetrating our cells.

Intestinal organoids, the one on the right is infected with the coronavirus SARS-CoV-2. The coronavirus is colored white, the organoids themselves are colored blue and green. © Joep Beumer, Copyright Hubrecht Institute

More tests

The observations made in this study provide definite proof that SARS-CoV-2 can replicate in cells of the gastrointestinal tract,” says Bart Haagmans from Erasmus MC. “However, we don’t yet know if SARS-CoV-2 present in the intestines of COVID-19 patients plays a significant role in transmission. Our findings indicate that we should look into this possibility more closely.”

Since not everyone with COVID-19 will necessarily present with any symptoms, and since viruses have also been detected in the stool of patients who had no respiratory symptoms, “special attention may be warranted” in patients with gastrointestinal symptoms, the scientists emphasize. More comprehensive tests involving not only nasal and throat swabs, but also rectal swabs or stool samples are likely to be needed.

The researchers are currently exploring the differences between pulmonary and intestinal infections by comparing pulmonary and intestinal organoids infected with SARS-CoV-2.