A second pathway into cells for SARS-CoV-2: New understanding of the neuropilin-1 protein could speed vaccine research

The spike protein on the surface of SARS-CoV-2 must bind to proteins on the surface of human cells in order to trigger infection. KTSDESIGN / SCIENCE PHOTO LIBRARY / Getty Images
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When it comes to how the coronavirus gets into a cell, it takes three to tango. The dance began with the ACE2 receptor, a protein found on human cells that allows SARS-CoV-2, the virus that causes COVID-19, to invade and infect the cell. But now a new dance partner enters - another protein - that is present on human cells. This tango of three proteins - two human and one viral - enhances SARS-CoV-2's ability to enter human cells, replicate, and cause disease.
COVID-19 has crippled health systems and the economy around the world. Tremendous efforts are being made to develop vaccines and other therapies to combat this virus. However, for this effort to be successful, it is important to understand how the virus gets into cells. To this end, in two articles published in Science, two teams independently discovered that a protein called neuropilin-1 receptor is an alternative door for SARS-CoV-2 to enter and infect human cells. This is a big breakthrough and a surprise, as scientists believed that Neuropilin-1 played a role in helping neurons make the right connections and support blood vessel growth. Prior to this new research, no one suspected that Neuropilin-1 could be a door for SARS-CoV-2 to enter the nervous system.
My colleagues and I were particularly intrigued by these reports because, as neuroscientists studying how pain signals are triggered and transmitted to the brain, we were also studying the activity of Neuropilin-1. In a recent article, our team showed how Neuropilin-1 is involved in pain signals and how the SARS-CoV-2 virus, when attached to it, blocks pain transmission and relieves pain. The new work shows that Neuropilin-1 is an independent door for the COVID-19 virus to infect cells. This discovery provides insight that may reveal ways to block the virus.
Neuropilin-1 helps SARS-CoV-2 with boarding
A protein called Spike, found on the outer surface of SARS-CoV-2, enables this virus to attach to protein receptors on human cells. Both research teams realized that a tiny piece of spike was similar to regions of human protein sequences known to bind to neuropilin receptors, and they realized that neuropilin-1 may be critical in infecting cells.
James L. Daly of Bristol University and colleagues demonstrated this using a technique called X-ray crystallography, which allows researchers to see the three-dimensional structure of the spike protein with single atom dissolution, as well as other biochemical approaches.This short sequence of spike is on Neuropilin-1 bound.
In experiments in the laboratory, the SARS-CoV-2 virus was able to infect fewer human cells that lacked neuropilin-1.
In cells with both the ACE2 and the Neuropilin-1 protein, the SARS-CoV-2 infection was greater than in cells with either of the two “doors” alone.
Daly and colleagues showed that SARS-CoV-2 could infect fewer cells when they used a small molecule called EG00229 or antibodies to block the spike protein's access to Neuropilin-1.
The neuropilin-1 receptor helps in virus infection of cells
Using similar methods, a team led by German and Finnish researchers came to the same results as the first study. In particular, this team showed that Neuropilin-1 was critical for the SARS-CoV-2 virus to invade and infect cells.
By using an antibody to block a region of the Neuropilin-1 receptor protein, the researchers showed that SARS-CoV-2, obtained from COVID-19 patients, could not infect cells.
In another experiment, Ludovico Cantuti-Castelvetri from the Technical University of Munich and colleagues bound silver particles to synthetic spike proteins produced in the laboratory and found that these particles can penetrate cells that have neuropilin-1 on their surfaces. When they performed the same experiments on live mice, they found that the silver particles invaded cells that line the nose. The researchers were surprised to discover that the spike protein can also penetrate neurons and blood vessels in the brain.
Cantuti-Castelvetri and colleagues, using tissues from human autopsies, found that neuropilin-1 was present in the cells lining the human airways and nasal passages, while the ACE2 protein was not. This shows that Neuropilin-1 provides an independent door for the COVID-19 virus to infect the cells.
In addition, cells lining the nasal passages of COVID-19 patients who were positive for Neuropilin-1 were also positive for the spike protein. These results confirmed that Spike uses the Neuropilin-1 protein to infect human cells in regions of the body where ACE2 is absent.
Neuropilin-1 can block viruses, cancer, and pain
In a surprising discovery recently reported by our laboratory, we found that the SARS-CoV-2 spike protein has an analgesic effect. Even more surprising was the finding that this analgesia affected the neuropilin-1 receptor.
We have shown that Spike prevents a protein from binding to Neuropilin-1, thereby blocking pain signals and providing pain relief. This is because this protein, called vascular endothelial growth factor A (VEGF-A), which is produced by many cells in the body, under normal circumstances binds to neuropilin-1 and triggers the process of pain signaling by exciting neurons that cause them transmit pain reports.
So the virus revealed a potential new target - the neuropilin-1 receptor - to treat chronic pain. If we can now decipher how Neuropilin-1 contributes to pain signaling, we can aim to find ways to block pain.
In our laboratory, we are now using the possibilities in which Spike uses Neuropilin-1 to develop new pain relievers. In this report on the BioRxiv preprint server, we identified a number of new compounds that bind to Neuropilin-1 in a way that mimics Spike. These molecules can disrupt neuropilin-1 function including the entry of the SARS-CoV-2 virus and block pain signals and even cancer growth.
More dance partners will follow
The studies by Daly and colleagues and Cantuti-Castelvetri and colleagues are shifting our shared focus to Neuropilin-1 as a potential new target for COVID-19 therapies.
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These studies also have implications for the development of vaccines against the spike protein. Perhaps the most important implication is that Spike's Neuropilin-1 binding region should be targeted for COVID-19 prevention. Because a number of other human viruses, including Ebola, HIV-1, and highly virulent strains of avian influenza, also share this signature sequence from Spike, Neuropilin-1 can be a promiscuous mediator for virus entry.
But it seems that the tango is not over yet. More dance partners have emerged. PIKFyve kinase and CD147 - two proteins - have also been shown to bind Spike and facilitate virus entry. It remains to be seen whether these new partners will take center stage or will play second fiddle after ACE2 and Neuropilin-1.
This article was republished by The Conversation, a non-profit news site dedicated to exchanging ideas from academic experts. It was written by: Rajesh Khanna, University of Arizona and Aubin Moutal, University of Arizona.
Continue reading:
SARS-CoV-2 infection can block pain and open unexpected new avenues for pain reliever research
What is the ACE2 receptor, how is it linked to the coronavirus, and why could it be key in treating COVID-19? The experts explain

The authors do not work for any company or organization that would benefit from this article, and do not consult with or obtain funding from stocks. You have not disclosed any relevant affiliations beyond your academic appointment.

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