The Sars-CoV-2 coronavirus can also penetrate the brain and infect neurons there. So far, however, it has been unclear how the virus gets into these brain cells, because they usually lack the appropriate docking sites. Now a study reveals that the coronavirus uses neural nanotunnels to do this. These connecting lines between cells are normally used for the intercellular transport of substances, but the corona virus can also use these tunnels to penetrate directly into the neurons. The experiments also revealed that the virus promotes the formation of such nanotunnels – and thus accelerates its spread in the brain.
Whether olfactory disorders, forgetfulness, “brain fog” or similar symptoms: Many patients with Covid-19 and Long-Covid suffer from neurological deficits during and after infection with the coronavirus. At the beginning of the pandemic, there was a suspicion that Sars-CoV-2 could also attack nerves and the brain. This was also supported by the fact that virus particles could be detected in the brains of some patients who died from Covid-19. In addition, studies with brain organoids showed that the coronavirus can also multiply in brain cells. However, it remained unclear how the pathogen got into these cells. Because unlike many body cells, most neurons do not have an ACE2 receptor on their cell surface – the docking point that the coronavirus needs to penetrate the cell.
From one cell type to another
Anna Pepe from the Institut Pasteur in Paris and her colleagues have now examined these questions in more detail. For their study, they first added Sars-CoV-2 to the nutrient solution of a neuron cell culture. As expected, the viruses did not manage to penetrate the brain cells – they lacked the portal of entry in the form of the ACE2 receptor. “This confirms that neuronal cells cannot be infected through a receptor-based mechanism,” explains the team. However, this was different when the neurons were cultured together with virus-susceptible epithelial cells: 24 hours after the addition of Sars-CoV-2, a third of the brain cells were already infected with the coronavirus, after 48 hours it was up to 62 percent. “Neural cells can therefore be infected with the coronavirus if they occur together with susceptible cell types,” write Pepe and her colleagues.
But how does the transmission take place? Further analysis revealed that intercellular nanotunnels had formed between the different cells. “Nanotunnels are thin, membranous and actin-containing conduits that enable the direct transport of cellular cargo such as organelles, amyloid proteins and also virus particles between distant cells,” the scientists explain. Because these tunnels lead into the interior of the connected cells, these “cargo pieces” do not first have to pass through membrane channels or receptors on the cell surface. This is exactly what the coronavirus is taking advantage of.
Via nanotunnels into the cell
In the experiments, Pepe and her team were able to detect both complete virus particles in such nanotunnels and the Sars-CoV-2 replication complexes formed by proteins. The coronavirus can therefore use these cellular tunnels to get from a vulnerable, infected cell to cell types that are not normally accessible. This direct, receptor-independent transport was also confirmed by a supplementary test in which the researchers blocked all ACE2 docking sites with an antibody. After 48 hours, in the co-culture permeated by nanotunnels, just as many neurons were infected with the coronavirus as in untreated control cultures.
“This confirms that Sars-CoV-2 can penetrate non-permissive cells through direct cell-to-cell contact,” say Pepe and her team. These results could therefore explain how the corona virus can also affect our brain cells. Apparently, it uses the nanotunnels that reach from the other cell types in the brain to the neurons. As the experiments also showed, the virus promotes the formation of such connecting tunnels and makes them more stable and longer. In infected mixed cultures, the percentage of cells coupled via nanotunnels doubled, as the researchers found. “In summary, we show that Sars-CoV-2 can hijack the nanotunnels in order to spread through the connected cells,” write Pepe and her colleagues.
Source: Anna Pepe (Institut Pasteur, Paris) et al., Science Advances, doi: 10.1126/sciadv.abo017