Researchers are growing miniature organs in the laboratory to study how the new coronavirus, SARS-CoV-2, wreaks havoc on the body. Studies with these organoids are revealing the virus’s versatility in invading organs, from the lungs to the liver, kidneys, and intestine. These mini-organs are also exploring what medicines could be used to treat people.

Doctors know from hospitalized patients and autopsies that SARS-CoV-2 can have a devastating effect on organs. But it is unclear whether some of this damage is caused directly by the virus or by secondary complications of the infection. Several groups are conducting organoid studies to find out where the virus travels in the body, what cells it infects, and what damage it causes.

“The beauty of organoids is that they simulate true tissue morphology,” says Thomas Efferth, a cell biologist at Johannes Gutenberg University in Mainz.

Virologists often study viruses by using cell lines or animal cells grown in a Petri dish. But they are not very helpful in SARS-CoV-2 infection, because they do not mimic what happens in the body, the researchers say.

The organs better demonstrate what the coronavirus does in human tissues, explains Núria Montserrat, a stem cell biologist at the Institute of Bioengineering of Catalonia in Barcelona. They can be grown to include multiple cell types and take the shape of the original organ in weeks, Montserrat says. They are also less expensive than animal models, and avoid the ethical concerns they raise.

However, studies on the effects of SARS-CoV-2 on organoids have limitations because they do not reflect the interference that occurs in the body between organs, which means that the findings should be validated in animal models and clinical studies, he says. Bart Haagmans, virologist at the Erasmus Medical Center in Rotterdam.

In the airways

One of the key pieces of information that organoids provide is how SARS-CoV-2 works in cells of the respiratory system, from the upper respiratory tract to the lungs.

Kazuo Takayama, a stem cell biologist at Kyoto University, and his collaborators have developed bronchial organoids with four cell types, from frozen cells in the outer bronchial layer, or epithelium. When his team infected those organoids with SARS-CoV-2, they discovered that the virus mainly targeted stem cells that replenish epithelial cells, known as basal cells, but they did not readily enter bronchiolar, or Clara, exocrine cells. they are protective. The team, which published their work on bioRxiv, now plans to study whether the virus can spread from basal cells to other cells.

From the upper respiratory tract, the virus can enter the lungs and cause respiratory failure, a serious complication of COVID-19. Using lung organoids, Shuibing Chen, a stem cell biologist at Weill Cornell Medical Center in New York, has shown that some cells die after being infected, and that the virus induces the production of proteins known as chemokines and cytokines. , which can trigger an exaggerated immune response. Many people with severe COVID-19 experience an immune reaction known as a cytokine storm that can be fatal.

But Chen, who also published his results on bioRxiv, explains that the reason for the death of lung cells in patients remains shrouded in mystery: it is unknown whether it is due to the damage itself caused by the virus, self-induced destruction, or they are engulfed by certain immune cells. “We know that cells [pulmonares] they die but we don’t know how, ”explains Chen, whose approach to creating organoids was different from Takayama’s. Instead of culturing them from adult cells, she used pluripotent stem cells, which can become any type of cell in the body. Organoids cultured in this way offer the potential to include more cell types, though the end result is less mature tissue, so it might not represent adult tissue, says Chen, who is currently culturing lung organoids with immune cells.

Through the blood

From the lungs, SARS-CoV-2 can spread to other organs, but the researchers didn’t know exactly how it managed to get there until Montserrat and his collaborators published a study in Cell in May. In organoid experiments, also created from pluripotent stem cells, they showed that SARS-CoV-2 can infect the endothelium (the cells that line the blood vessels), allowing it to leak into the blood and circulate throughout the body. . Pathology reports on the blood vessels of people with COVID-19 also support this hypothesis, says Josef Penninger, a genetic engineer at the University of British Columbia in Vancouver and co-author of the study.

Organoid research indicates that once in the blood, the virus can directly infect various organs, including the kidney, Penninger and Montserrat argue. Although the virus infected the kidney organoids they grew and some of their cells died, the researchers are not sure that this is the direct cause of the kidney dysfunction seen in some patients.

Another liver organoid study found that the virus can infect and destroy cells that contribute to bile production, known as cholangiocytes. Many researchers thought that the liver damage seen in people with COVID-19 is caused by an overactive immune response or the side effects of the drugs, says Bing Zhao, a cell biologist at Fudan University in Shanghai, who published his results in Protein & Cell. Their work “suggests that the virus directly attacks liver tissue, which can cause organ damage,” explains Zhao.

The virus can also replicate in the cells that line the small and large intestines, known as enterocytes, according to a Science study that used intestinal organoids.

Although these findings are illuminating, the use of organoids to study the interaction between the virus and the host is still in its infancy, says Haagmans, who developed the intestinal organoids. “It is too early to know how relevant they are,” he says. More complex organoid systems are needed to better understand how the virus interacts with the immune system and causes damage to the body, the researchers say.

“We are pretty sure now that the virus that causes COVID-19 can infect other tissues beyond the lungs and make a significant contribution to the disease,” says Penninger. But the more serious damage, such as that affecting the kidneys and heart, is likely due to a combination of viral infection and an exaggerated immune response, he says.

Drug test bench

Scientists are also exploring whether organoids can be used to model the body’s response to drugs. The hope is that they will serve to test the efficacy of possible treatments for COVID-19 (some of which have already been hastily used in clinical trials) without the need for extensive testing on animal and cell models.

“Due to time constraints, numerous clinical trials were designed based on existing knowledge of other coronaviruses and were undertaken without careful prior evaluation in models,” Chen notes. “As a result, many of them have failed.”

Chen examined about 1,200 medications approved by the United States Food and Drug Administration indicated for other diseases and found that the oncropharmaceutical imatinib suppressed SARS-CoV-2 in lung organoids. Since then, several human clinical trials have been initiated to study this treatment on COVID-19.

Other groups are also examining the effect of existing drugs against the coronavirus using organoids, with some success 2,8. “We will only know at the end of this process the predictive value of these systems to know the efficacy of the drugs,” says Haagmans. “It is a long-term process.”

Smriti Mallapaty / Nature News

Article translated and adapted by Research and Science with permission from Nature Research Group.

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