Researchers at the University of California San Diego School of Medicine and the Rady Children’s Institute for Genomic Medicine have created a stem cell model that shows a possible entry route for SARS-CoV-2, the virus that causes COVID-19, into the human brain.

The results will be published in the online edition of July 9, 2021 Natural medicine.

“Clinical and epidemiological observations suggest that the brain may be implicated in SARS-CoV-2 infection,” said senior author Joseph Gleeson, MD, Rady Professor of Neuroscience at the UC San Diego School of Medicine and director of the neuroscientific research at the Rady Children’s Institute for Genomic Medicine.

“The prospect of COVID19-induced brain damage has become a major concern in ‘long-term COVID’ cases, but human neurons in culture are not susceptible to infection. Previous publications suggest that the cells that make up the spinal fluid could be infected with SARS-CoV-2, but other routes of entry seemed likely. “

Gleeson and colleagues, who included both neuroscientists and infectious disease specialists, confirmed that human nerve cells are resistant to SARS-CoV-2 infection. However, recent studies suggested that other types of brain cells could serve as the “Trojan horse”.

Pericytes are specialized cells that wrap around blood vessels – and carry the SARS-CoV2 receptor. The researchers introduced pericytes into three-dimensional neural cell cultures – organoids of the brain – to create “assemboids,” a more complex stem cell model of the human body. These assemloids contained many types of brain cells in addition to pericytes and showed robust infection by SARS-CoV-2.

The coronavirus was able to infect the pericytes, which served as localized factories for the production of SARS-CoV-2. These locally produced SARS-CoV-2s could then spread to other cell types and cause widespread damage. Using this improved model system, they found that the supporting cells known as astrocytes were the primary target of this secondary infection.

The results, Gleeson said, suggest that one potential route for SARS-CoV-2 to get into the brain is through blood vessels, where SARS-CoV-2 can infect pericytes and then SARS-CoV-2 can spread to other brain types Cells.

“Alternatively, the infected pericytes could lead to inflammation of the blood vessels with subsequent blood clotting, stroke or bleeding, complications that are observed in many patients with SARS-CoV-2 who are admitted to intensive care units.”

Researchers now plan to focus on developing improved assemloids that contain not only pericytes but also blood vessels that can pump blood to better model the intact human brain. These models, says Gleeson, could provide better insights into infectious diseases and other diseases of the human brain.

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Co-authors are: Lu Wang, David Sievert and Sangmoon Lee, UC San Diego and Rady Children’s Institute for Genomic Medicine; Alex E. Clark and Aaron F. Carlin, UC San Diego; Hannah Federman, UC San Diego, Rady Children’s Institute for Genomic Medicine, and Rutgers University; and Benjamin D. Gastfriend, Eric V. Shusta, and Sean P. Palecek, University of Wisconsin-Madison.

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