- Scientists already know that SARS-CoV-2 uses the ACE2 receptor to infect human cells.
- However, a new breakthrough explains how the virus uses a receptor called neuropilin-1 to infect human cells.
- This receptor is widespread in many human tissues.
As the number of confirmed global SARS-CoV-2 infections nears 44 million, scientists are still battling to understand what makes the virus so effective and transmissive.
But a new study may have the answer: The virus is using a second protein, called neuropilin-1, to facilitate entry into human cells.
The first receptor, angiotensin-converting enzyme 2 (ACE2), was discovered during the early stages of the pandemic, and scientists came to understand how the virus used it to bind to the surface of cells. An enzyme called type II transmembrane serine protease (TMPRSS2) was also found to be crucial for gaining entry.
The findings of the researchers, from the Technical University of Munich in Germany and the University of Helsinki in Finland, were published in Science.
"To efficiently infect human cells, SARS-CoV-2, the virus that causes Covid-19, is able to use a receptor called neuropilin-1, which is very abundant in many human tissues, including the respiratory tract, blood vessels and neurons," a news release by the University of Helsinki stated.
Comparing viral genomes
"The starting point of our study was the question why SARS-CoV, a coronavirus that led to a much smaller outbreak in 2003, and SARS-CoV-2, spread in such a different way even if they use the same main receptor ACE2," said University of Helsinki virologist Ravi Ojha.
Part of what led to the researchers’ discovery was comparing the two viral genomes (the virus' hereditary information) and analysing the viral surface proteins, the "spikes", that anchor the virus to the cells.
What they found was that SARS-CoV-2 had picked up sequences responsible for producing a prickly array of hooks to grip onto host tissues – which was not used by other pathogens.
"Compared to its older relative, the new coronavirus had acquired an 'extra piece' on its surface proteins, which is also found in the spikes of many devastating human viruses, including Ebola, HIV, and highly pathogenic strains of avian influenza, among others," said Olli Vapalahti, a virologist from the University of Helsinki.
After working together with colleagues around the world, the team directed their attention to neuropilin-1.
Neuropilin-1's primary function
Typically, as a cell-surface receptor, neuropilin-1 plays a role in responding to growth factors important in tissue development. However, it can also act as a convenient handle for viruses by allowing them to attach onto host cells long enough to break in.
The researchers used electron microscopy, monoclonal antibodies, examined tissue samples expressing the receptor taken from deceased Covid-19 patients, and conducted an experiment involving mice to confirm their suspicions of its role in facilitating SARS-CoV-2's entry into the nervous system.
"If you think of ACE2 as a door lock to enter the cell, then neuropilin-1 could be a factor that directs the virus to the door," explained Giuseppe Balistreri, a virologist at the Faculty of Biological and Environmental Sciences at the University of Helsinki.
"ACE2 is expressed at very low levels in most cells. Thus, it is not easy for the virus to find doors to enter. Other factors such as neuropilin-1 might help the virus finding its door."
Since neuropilin-1 is expressed in large amounts in nerve tissues within the nasal cavity, it means that the new coronavirus has a convenient advantage in infecting human cells.
"Currently, our laboratory is testing the effect of new molecules that we have specifically designed to interrupt the connection between the virus and neuropilin," said Balistreri.
"Preliminary results are very promising and we hope to obtain validations in vivo (research done within a living organism) in the near future."