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A recent three-part study concludes that SARS-CoV-2 can infect nerve cells and interfere with blood flow in the central nervous system.
COVID-19 continues to have devastating effects on the short and long term health of millions of people around the world.
Because SARS-CoV-2, the virus that causes the disease, is relatively new territory, researchers are still studying how it works in various organs.
A team of scientists, many from the Yale School of Medicine in New Haven, CT, recently provided evidence that SARS-CoV-2 can directly infect central nervous system (CNS) cells and cause tissue damage.
The results appear in the Journal of Experimental Medicine.
SARS-CoV-2 infects lung tissue by binding to angiotensin converting enzyme 2 (ACE 2) receptors on the surface of cells. Once it binds to a cell, the virus can enter it and cause respiratory symptoms such as shortness of breath and a dry cough.
However, recent studies have shown that the virus can also infect cells of the CNS, which includes the brain and spinal cord.
This helps explain the growing number of patients with neurological symptoms, including dizziness, confusion, stroke, and coma.
The present study builds on previous research by analyzing the mechanisms of nerve cell infection. To explore the extent and impact of the infection, the team used three different brain models: human brain organoids, genetically engineered mice, and autopsies of people with deceased COVID-19.
The study first looked at the potential of SARS-CoV-2 to infect the brain using human brain organoids – 3D models produced in a lab from stem cells from healthy individuals.
Scientists also used models of brain organoids to analyze similar questions of neuronal infection during the 2015-2016 Zika virus outbreak.
In the present study, organoids accumulated SARS-CoV-2 positive cells in specific brain regions, proving that the virus can infect neurons and replicate.
Areas near these infected cells also reported increased levels of cell death. However, it turned out that the majority of these dead cells had not been infected. Cells were susceptible to infection or cell death, but rarely to both.
To explore this question further, the researchers compared the genes of infected cells to those of nearby uninfected cells. They found that infected cells exhibited an increased metabolism that allowed the virus to replicate more efficiently and potentially limit the oxygen supply to surrounding cells.
These findings suggest that the virus has the ability to alter cell metabolism to create an environment in which infected cells thrive and neighboring cells are unable to survive.
The organoid model also showed that the ACE2 receptor allows the virus to enter brain cells, much like it does in the lungs. The result was surprising, as it was not previously clear whether CNS cells produced ACE2 receptors.
When researchers introduced antibodies to the organoid to block the protein, the virus was unable to bind to the protein, and cell infection rates declined.
Next, the researchers used a mouse model to observe a CNS infection in the context of a whole organism. To closely replicate the infection in humans, they genetically engineered mice to produce human ACE2 proteins.
After infecting the mice, the scientists detected high levels of infected nerve cells. These levels were associated with significant changes in blood vessels – changes that could disrupt the flow of oxygen to the brain.
The study also compared the effects of CNS infection and lung infection in mice and determined that CNS infection was significantly more fatal. Even with lower doses of the virus, neuronal infection resulted in weight loss and death in the mice.
Finally, the researchers looked at brain regions of three patients who died from severe complications from COVID-19. All had suffered from respiratory failure and had been admitted to the intensive care unit.
In infected areas of the brain, there were signs of tissue damage and cell death in the form of ischemic infarcts – areas of dead tissue caused by lack of blood flow.
These infarcts were the result of several disturbances of oxygen and blood flow. They were similar to those the researchers observed in brain and murine organoid models, which also showed evidence of oxygen deprivation.
“Overall, our study provides [a] clear demonstration that neurons can become a target for SARS-CoV-2 infection, with devastating consequences of localized ischemia in the brain and cell death. ”
– Principal co-author Dr. Kaya bilguvar
Understanding what factors increase susceptibility to this infection will require more research, but the present study has provided insight into the more detailed mechanisms of the CNS in relation to COVID-19.
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