The coronavirus SARS-CoV-2 can spread from one cell to another through microscopic connections between cells, tunneling nanotubes (TNT). This may be a mechanism that may explain how SARS-CoV-2 can get into the brain, despite the fact that most brain cells lack the necessary ACE-2 receptor on their surface. The virus piggybacks on the TNT connections. That write researchers Anna Pepe and Chiara Zurzolo from the Institut Pasteur in Paris in Science Advances.
Other researchers have previously demonstrated the presence of SARS-CoV-2 in the brain of a deceased Covid patient. In addition, it is also known that a corona infection can cause numerous neurological symptoms, ranging from fatigue and concentration problems to loss of smell and taste. But it was a mystery how the coronavirus managed to infect nerve cells, most of which lack the ACE-2 receptor.
Thin offshoots
Zurzolo’s research group decided to see whether the infection could be transmitted from lung cells to nerve cells via tiny nanotubes. These are elongated thin extensions of the cell that make connections between them. Previous research had already established that other viruses, including HIV, herpes and the flu virus, could move to other cells through such tubes. An alternative method of infection, which in this case would also make it possible for corona to infect cells without an ACE-2 receptor.
In their experiments, the researchers showed that cultured nerve cells did not become infected when they added SARS-CoV-2. Lung cells that have many ACE-2 receptors on their cell surface did become infected. But if the researchers grew both types of cells together in one container and added virus, the nerve cells did become infected. The same experiment with the remaining dead lung cells did not result in infection of the nerve cells, an indication that the virus transmission must be an active process that requires living lung cells.
Further research also showed that infection with SARS-CoV-2 prompts the lung cells to make extra TNTs. They made them much more among themselves, but also with the brain cells if they were in the same container.
One of the researchers in the team is the Dutchman Matthijn Vos, who specializes in cryo-electron microscopy. “With this technique we can make a CT scan of cells, as it were, so that we can see very precisely what is happening in and around the TNTs. Thus we could see that TNTs were indeed formed between the lung cells and brain cells. And that there were sometimes virus particles on and in those TNTs.”
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To the nerve cells
It is not yet clear how exactly the infection can travel via the nanotubes from lung cells to nerve cells. “The name tunneling nanotube suggests that the virus or its parts pass through it. Via the tunnel, the open connection between two cells, genetic material of the virus can move, but also virus factories, a set of virus proteins, or even complete virus particles. But the point is, it doesn’t have to go through the tube. We occasionally see the virus in the tunnel, but we don’t know whether it actually crosses that way.”
There is another possibility, says Vos: “We also saw virus particles on the outside of the tubes. This may indicate that the ACE2 receptor moves from the lung cell through the membrane of the tube to the nerve cell. As a result, the nerve cell still becomes receptive to SARS-CoV-2.”
To find out how the infection moves, the researchers would like to follow the transport of a live coronavirus via a TNT ‘live’. But that is only possible with a microscope that is located in a BSL-3 laboratory. This is a laboratory with a very strict safety regime, which is still required for working with SARS-CoV-2, explains Vos. “Globally there are only a few microscopes in such a highly secured lab and access to them is very limited. We hope to start building our own facility next year.”
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