In order to get into our cells, the coronavirus first has to dock on certain “door openers”. Now it has been shown that Sars-CoV-2 uses another surface protein of human cells in addition to the already known ACE2 receptor: Neuropilin-1. This protein is found in higher density on mucous membrane cells, for example in the nose, than ACE2. This could explain why these tissues in particular are so susceptible to the coronavirus and why Sars-CoV-2 was able to spread faster and more strongly than its predecessor Sars.
Sars-CoV-2 can affect significantly more tissue types and organs than initially assumed. In addition to the cells of the respiratory tract and lungs, the tissues of the intestines, kidneys, blood vessels and the nervous system have now proven to be susceptible to infection. As we now know, the virus uses a specific surface protein of human cells, the so-called angiotensin-converting enzyme 2 (ACE2), to enter the cells. The virus binds to this docking site with part of its spike protein and this binding changes the cell membrane so that it can penetrate. A further surface protein, the cofactor TMPRSS2, “assists” him. The predecessor of Sars-CoV-2, the causative agent of the Sars pandemic of 2002/2003, also used the ACE2 receptor as a gateway into the cells. But although both viruses use the ACE2 receptor, Sars-CoV was far less transmittable and could only affect the lower respiratory tract, but not other types of tissue.
Second docking point on the cell
A research team led by Mikael Simons from the Technical University of Munich could have found an explanation for this difference. “The starting point of our study was the question of why Sars-CoV and Sars-CoV-2, which both use ACE2 as receptors, cause different diseases,” explains Simons. In search of an answer, the researchers compared the structure of the spike protein of the two viruses. There was a difference: “The SARS-CoV-2 spike protein differs from its older relative in that it has a furin cleavage site,” explains Simons. When the spike protein unfolds at this point, it reveals a specific amino acid sequence. “Similar cleavage sites can be found in the spike proteins of many other highly pathogenic human viruses. When we realized that this furin cleavage site was present in the Sars-CoV-2 spike protein, we thought that this could lead us to the answer, ”said Simons.
It is known from the sequence exposed by the furin cleavage site that it can bind to other receptors on the cells, the so-called neuropilins. This raised the question of whether the current coronavirus might also use these cell surface proteins as additional docking points. To clarify this, the scientists carried out cell culture tests. To do this, they expose cells to the virus that either only carried ACE2 and TMPRSS2, only Neuropilin-1, or all three receptors. It was found that the virus was unable to infect the cells with Neuropilin-1 alone. But when Neuropilin was present in addition to ACE2 and TMPRSS2, the infection rate was significantly higher than for cells only with the two known docking sites. The researchers conclude that Neuropilin-1 is able to promote the infection in the company of ACE2.
Explanation of the vulnerability of so many tissues
This helping role of Neuropilin-1 could explain why the coronavirus can affect so many different tissues and organs – including those that carry very little ACE2. “If you imagine ACE2 as the entrance door into the cell, then neuropilin-1 could be a factor that steers the virus to the door,” explains Simons. “ACE2 is expressed in very small amounts in most cells. It is therefore not easy for the virus to find doors to penetrate. ”Neuropilin-1 could, so to speak, show him these doors. However, the researchers do not rule out that Sars-CoV-2 can penetrate cells even without ACE2 in the event of a very high viral load. To check the role of Neuropilin-1, the scientists also examined tissue samples from deceased Covid-19 patients: “We wanted to find out whether cells in the body that were equipped with Neuropilin-1 are actually infected with Sars-CoV-2, and we found them firmly that this is the case, ”reports Simons. “At the moment, however, we can only speculate about the molecular processes that play a role. Presumably Neuropilin-1 catches the virus and directs it to ACE2. “
The newly discovered door opener Neuropilin could also play a decisive role in smuggling Sars-CoV-2 into the nervous system and the brain and thus triggering olfactory disorders and neurological complications. Tests with mice have shown that Neuropilin-1 enables the transport of pseudovirus nanoparticles from the nasal mucosa to the central nervous system. “We were able to determine that neuropilin-1 promotes transport to the brain under the conditions of our experiments,” says Simons. However, it is still unclear whether this process will also take place in Covid 19 patients. “It is very likely that this transport route is suppressed by the immune system in most patients,” says the researcher.
In theory, the new findings could also offer a new approach to warding off the coronavirus. In the first tests on cell cultures, a blockade of Neuropilin-1 by antibodies suppressed an infection of the cells with SARS-CoV-2. However, before this observation becomes a possible treatment, many tests still have to be carried out, as the researchers emphasize: “It is currently too early to speculate whether blocking neuropilin could be a possible therapeutic approach. Future studies will have to deal with this, ”says Simons.
Source: Ludovico Cantuti-Castelvetri (TU Munich) et al., Science, doi: 10.1126 / science.abd2985