Novel coronavirus, SARS-CoV-2. Photo via @UCSDJacobs

UC San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine researchers announced Friday they have produced a stem cell model showing a potential entry route for the COVID-19 virus into the human brain.

The findings on the SARS-CoV-2 virus were published in the July 9 online issue of Nature Medicine.

“Clinical and epidemiological observations suggest that the brain can become involved in SARS-CoV-2 infection,” said Dr. Joseph Gleeson, research senior author and a Rady neuroscience professor at UC San Diego School of Medicine.

“The prospect of COVID19-induced brain damage has become a primary concern in cases of ‘long COVID,’ but human neurons in culture are not susceptible to infection,” said Gleeson, also neuroscience research director at the Rady Children’s Institute for Genomic Medicine. “Prior publications suggest that the cells that make the spinal fluid could become infected with SARS-CoV-2, but other routes of entry seemed likely.”

Gleeson and his colleagues, which included neuroscientists and infectious disease specialists, confirmed that human neural cells are resistant to SARS-CoV-2 infection. At the same time, recent studies hinted that other types of brain cells might serve as a “Trojan horse.”

According to the findings, pericytes — specialized cells that wrap around blood vessels — carry the SARS-CoV-2 receptor.

Researchers introduced pericytes into three-dimensional neural cell cultures, called brain organoids, to create “assembloids,” or a more sophisticated stem cell model of the human body.

The assembloids contained many types of brain cells, along with pericytes, and showed “robust infection” by SARS-CoV-2.

The coronavirus was able to infect the pericytes, which served as localized factories for production of SARS-CoV-2, according to the researchers. In turn, the locally produced SARS-CoV-2 could then spread to other cell types, leading to widespread damage.

Via an improved model system, researchers found that the supporting cells known as astrocytes were the main target of this secondary infection.

Gleeson said the results indicate that one potential route of SARS-CoV-2 into the brain is through blood vessels, where SARS-CoV-2 can infect pericytes, and then spread to other types of brain cells.

“Alternatively, the infected pericytes could lead to inflammation of the blood vessels, followed by clotting, stroke or hemorrhages, complications that are observed in many patients with SARS-CoV-2 who are hospitalized in intensive care units,” Gleeson said.

Researchers said they now plan to focus on developing improved assembloids that contain pericytes and blood vessels capable of pumping blood to better model the intact human brain.

Gleeson added that these models could provide greater insight into infectious disease and other human brain disease.

Co-authors of the study were 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.

Research funding was provided by the Rady Children’s Hospital Neuroscience Endowment, the Burroughs Wellcome Fund, the Brain & Behavior Research Foundation NARSAD, the National Institutes of Health,  the National Science Foundation Graduate Research Fellowship Program, the UC San Diego Neuroscience Microscopy Core Facility and the UC San Diego IGM Core Facility.

The full study is available at www.nature.com.

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