Just when we thought the SARS-CoV-2 virus couldn’t get any more insidious, a new study from investigators at the Yale School of Medicine describes the mechanisms that allow the coronavirus to directly infect the central nervous system. The new study was performed using both mouse and human brain tissue, and the results were published recently in the Journal of Experimental Medicine through an article entitled “Neuroinvasion of SARS-CoV-2 in human and mouse brain.” The study authors are optimistic that their findings may help other researchers develop treatments for the various neurological symptoms associated with COVID-19.

“Understanding the full extent of viral invasion is crucial to treating patients, as we begin to try to figure out the long-term consequences of COVID-19, many of which are predicted to involve the central nervous system,” explained senior study investigator Akiko Iwasaki, PhD, a professor at Yale School of Medicine and an investigator at the Howard Hughes Medical Institute.

Although COVID-19 is considered to primarily be a respiratory disease, SARS-CoV-2 can affect many other organs in the body, including, in some patients, the central nervous system, where the infection is associated with a variety of symptoms ranging from headaches and loss of taste and smell to impaired consciousness, delirium, strokes, and cerebral hemorrhage.

Many questions about the virus remain to be answered, including whether SARS-CoV-2 can infect neurons or other types of brain cells. To address this question, Iwasaki and her colleagues analyzed the ability of SARS-CoV-2 to invade human brain organoids. The researchers found that the virus was able to infect neurons in these organoids and use the neuronal cell machinery to replicate. The virus appears to facilitate its replication by boosting the metabolism of infected cells, while neighboring, uninfected neurons die as their oxygen supply is reduced.

Credit: J Exp Med. 2021;218(3). doi:10.1084/jem.20202135

SARS-CoV-2 enters lung cells by binding to a protein called ACE2, but whether this protein is present on the surface of brain cells is unclear. Interestingly, the research team determined that the ACE2 protein is, in fact, produced by neurons and that blocking this protein prevents the virus from human brain organoids.

SARS-CoV-2 was also able to infect the brains of mice genetically engineered to produce human ACE2, causing dramatic alterations in the brain’s blood vessels that could potentially disrupt the organ’s oxygen supply. Central nervous system infection was much more lethal in mice than infections limited to the lungs, the researchers found.

“We used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain,” the authors wrote. “First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo.”

Finally, the researchers analyzed the brains of three patients who succumbed to COVID-19. SARS-CoV-2 was detected in the cortical neurons of one of these patients, and the infected brain regions were associated with ischemic infarcts in which decreased blood supply causes localized tissue damage and cell death. Microinfarcts were detected in the brain autopsy of all three patients.

An image of a human brain organoid shows numerous dying cells (green) surrounding neurons (gray) that have been infected by SARS-CoV-2 (red). [© 2021 Song et al. Originally published in the Journal of Experimental Medicine. https://doi.org/10.1084/jem.20202135]
“Our study clearly demonstrates that neurons can become a target of SARS-CoV-2 infection, with devastating consequences of localized ischemia in the brain and cell death,” noted co-senior study investigator Kaya Bilguvar, MD, an associate professor of genetics and director of the Yale Center for Genome Analysis. “Our results suggest that neurologic symptoms associated with COVID-19 may be related to these consequences and may help guide rational approaches to the treatment of COVID-19 patients with neuronal disorders.”

“Future studies will be needed to investigate what might predispose some patients to infections of the central nervous system and to determine the route of SARS-CoV-2 invasion into the brain and the sequence of infection in different cell types within the central nervous system that will help validate the temporal relationship between SARS-CoV-2 and ischemic infarcts in patients,” Iwasaki concluded.

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