Organoids and coronavirus
Miniature organs show how coronavirus affects the body
Mini organs reveal how the coronavirus ravages the body
Smriti Mallapaty, Nature
Translation: Inopressa
Scientists are growing miniature organs in the laboratory to understand how the new coronavirus affects the human body. Studies of these organoids show that the virus penetrates into a variety of organs, including the lungs, liver, kidneys and intestines. Researchers are also conducting experiments with various drugs in these mini-tissues in an attempt to understand whether such drugs can treat people.
Studying hospitalized patients and autopsy results, doctors realized that SARS-CoV-2 can have a devastating effect on human organs. But it is not yet clear whether these lesions are caused directly by the coronavirus, or by secondary complications due to infection. By examining organoids, numerous teams are trying to figure out how and where the virus moves in the body, which cells it infects, and what damage it causes.
"The benefit of studying organoids is that they resemble the true morphology of tissues," says cell biologist Thomas Efferth from Johannes Gutenberg University, in Mainz, Germany.
Virologists usually study viruses using cell lines or cultured animal cells in laboratory conditions. But it is impossible to simulate SARS-CoV-2 infection in such a high-quality way, because these cells do not simulate what is happening in the body.
Organoids better show what SARS-CoV-2 does to human tissue, says stem cell biology specialist Nuria Montserrat, who works in Barcelona, Spain in Catalan Institute of Bioengineering. It is possible to grow a variety of cell types, creating the shape of the original organ in a matter of weeks, she notes. In addition, it is cheaper than using animals, and there are no ethical problems.
However, SARS-CoV-2 studies on organoids have their drawbacks, since in this case it is impossible to take into account the interaction between organs. This means that the results should be tested on animals and in clinical trials, says virologist Bart Haagmans, who works at the Erasmus University Rotterdam Medical Center.
One of the key tasks of organoid research is to find out what the SARS-CoV-2 virus does to cells in the respiratory system, starting from the upper respiratory tract and ending with the lungs.
Specialist in stem cell biology from At Kyoto University, Kazuo Takayama and his colleagues created bronchial organoids of four types by taking frozen cells of the outer shell of the bronchial epithelium. When scientists infected SARS-CoV-2 organoids, they managed to find out that the virus mainly affects stem cells that reproduce cells of the lower layer of the epithelium, but it hardly penetrates into protective secretory cells. Scientists have posted the materials of their work on the bioRxiv website, and now they plan to find an answer to the question of whether the virus can spread from the cells of the lower layer of the epithelium to other cells.
From the upper respiratory tract, the virus can enter the lungs and cause respiratory failure, which is a serious complication of COVID-19. Using mini-lungs from a test tube, stem cell biology specialist Shuibing Chen from Weill Cornell Medical College showed that some infected cells die, and that the virus promotes the production of chemokine proteins and cytokines that cause a powerful immune response. Many people with a severe form of COVID-19 face an immune reaction called cytokine storm, which is deadly.
However, Chen, who also posted her results on bioRxiv, says it is not yet clear why human lung cells are dying. Maybe it's the result of exposure to the virus, maybe it's self-destruction, or maybe they are killed by immunocytes. "We know that cells die, but we don't know how," she says. Her approach to creating organoids differs from Takayama's method. Instead of creating them from adult cells, Chen used pluripotent stem cells, from which cells of any type can be created in the body. Organoids grown in this way may include more cell types, but the final tissue is less mature and is not an adult tissue, says Chen, who currently grows lung organoids on immunocytes.
From the lungs, SARS-CoV-2 can penetrate into other organs. However, scientists were not sure exactly how the virus was moving until Montserrat and colleagues published the results of their study on May 4. During experiments with organoids, also grown from pluripotent stem cells, they found out that SARS-CoV-2 can infect the endothelium (the layer of cells lining the inner surface of blood vessels), so that viral particles enter the blood and spread throughout the body. This hypothesis is confirmed by the results of autopsies of those who died from COVID-19 and the study of damaged blood vessels, says genetic engineer Joseph Penninger, who works in Vancouver, Canada in University of British Columbia and became the lead co-author of this study.
Studies on organoids indicate that once in the blood, the virus can directly infect several organs, including the kidneys. Although the virus infected the organoids of the kidneys, and some cells died, scientists do not know for sure whether this is a direct cause of renal dysfunction noted in some patients.
In another study on liver organoids, it was found out that the virus is able to infect and kill cholangiocytes cells that promote bile secretion. Many scientists believed that the liver damage noted in COVID-19 patients was caused by an excessive immune response or side effects from medications, says cell biologist Bing Zhao, who works in Shanghai at Fudan University. In his study, the results of which are published in the journal Protein and Cell, he concludes that the virus can directly attack liver tissue, and this causes its defeat.
The virus can also reproduce in enterocyte cells that make up the epithelium of the small and large intestine, as evidenced by the data of a study on intestinal organoids published in the journal "Science".
These studies are very informative, but the use of organoids to study the interaction of the host virus is still in its infancy, says Haagmans, who grew intestinal organoids. "It's too early to say how relevant they are," the scientist notes. More complex organoid systems are needed to better understand how the virus interacts with the immune system, causing damage to the body.
"Now we have a pretty firm belief that the virus causing COVID-19 can infect tissues outside the lungs and significantly worsen the disease," says Penninger. However, more serious outcomes of the disease associated with kidney and heart damage are probably caused by a combination of a viral infection and an excessive immune response, he explains.
Scientists also want to understand whether organoids can be used to simulate the effects of drugs on the human body. They hope that organoids can be used to test possible drugs from COVID-19. In some places, clinical trials are already being hastily conducted without large-scale checks on cells and animals.
"Due to the time factor, many clinical trials were prepared on the basis of existing knowledge about other coronaviruses, and they were conducted without careful evaluation on models," Chen says. "In the end, many of them failed."
Chen tested approximately 1,200 drugs approved by the FDA for the treatment of other diseases, and found that the anti-cancer drug imatinib suppresses the SARS-CoV-2 virus in lung organoids. After that, several clinical trials of this drug in humans began as a treatment for COVID-19.
Other research teams are also testing existing coronavirus drugs on organoids, achieving some success. "We will only know at the end of the process what the predictive value of these systems is for drug efficacy checks," says Haagmans. – It's a long process."
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