Researchers at University of California San Diego School of Medicine have built a stem cell model that helps explain how SARS-CoV-2 reaches the brain.
Clinical evidence suggests that SARS-CoV-2 can have an effect on the central nervous system, either directly or indirectly, however the mechanisms are unknown. Pericytes are perivascular cells that are thought to be SARS-CoV-2 infection locations in the brain.
Perivascular cells are cells that line the inside of capillary walls. The cells aid in the development of blood vessels and the control of immune cell entrance into the central nervous system (CNS).
In a new study, researchers from the University of California San Diego School of Medicine and the Rady Children’s Institute for Genomic Medicine have developed a stem cell model that shows how SARS-CoV-2, the virus that causes COVID-19, enters the brain.
The research found that PLCs inside cortical organoids served as viral ‘replication hubs,’ with the virus spreading to astrocytes and driving inflammatory type I interferon transcriptional responses, while typical cortical organoids exhibited minimal evidence of infection.
As a result, PLC-containing cortical organoids (PCCOs) constitute a new model that promotes astrocytic maturation as well as SARS-CoV-2 entry and replication in brain tissue; hence, PCCOs serve as a neural infection experimental model. According to the findings, one possible path for SARS-CoV-2 to enter the brain is through blood vessels, where it can infect pericytes and then spread to other types of brain cells.
Senior author Dr. Joseph Gleeson, MD, director of neuroscience research at the Rady Children’s Institute for Genomic Medicine and Rady Professor of Neuroscience at UC San Diego School of Medicine, stated, “Clinical and epidemiological observations suggest that the brain can become involved in SARS-CoV-2 infection.”
Gleeson added, “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.”
Despite the fact that SARS-CoV-2 infection has been modeled in various three-dimensional brain organoids, evidence suggests that most neural cells have little to no capacity for SARS-CoV-2 infection. However, the presence of any cells expressing ACE2 or other receptors may be enough to trigger infection prompting more research into the receptor expression profile and its impact on infection in the human neurovascular unit in vivo.
The PCCO SARS-CoV-2 infection model proposes an alternate route to infection based on clinical and experimental findings suggesting possible vascular entry and ACE2 expression in pericytes. The paper’s authors suggest that neurovascular unit component cell types could be added to the PCCO model to improve it even more, which could lead to new applications.
The study was published in Nature Medicine, on July 9th, 2021.
Wang, L., Sievert, D., Clark, A.E. et al. A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology. Nat Med (2021). https://doi.org/10.1038/s41591-021-01443-1
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