When it comes to how the coronavirus invades a cell, it takes three to tango. The dance began with the ACE2 receptor, a protein on human cells that allows SARS-CoV-2, the virus that causes COVID-19, to enter and infect the cell. But now enter a new dance partner – another protein – that is present on human cells. This tango of three proteins – two human and one viral – enhances the ability of SARS-CoV-2 to enter human cells, replicate and cause disease.
COVID-19 has crippled health care systems and economies worldwide. Extraordinary efforts are underway to develop vaccines and other therapies to combat this virus. But for these efforts to succeed, understanding how the virus enters cells is critical. To that end, in two papers published in Science, two teams independently discovered that a protein called the neuropilin-1 receptor is an alternative doorway for SARS-CoV-2 to enter and infect human cells. This is a major breakthrough and a surprise, because scientists thought neuropilin-1 played roles in helping neurons make the correct connections and aiding the growth of blood vessels. Before 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 who study how pain signals are triggered and transmitted to the brain, we were also probing the activity of neuropilin-1. In a recent paper our team showed how neuropilin-1 is involved with pain signals and how, when the SARS-CoV-2 virus attaches to it, it blocks pain transmission and relieves pain. The new work shows that neuropilin-1 is an independent doorway for the COVID-19 virus to infect cells. This discovery provides insights that may reveal ways to block the virus.
Neuropilin-1 helps SARS-CoV-2 get in
A protein called Spike that sits on the outer surface of SARS-CoV-2 allows this virus to attach to protein receptors of human cells. Recognizing that a tiny piece of Spike was similar to regions of human protein sequences known to bind to neuropilin receptors, both research teams realized that neuropilin-1 may be critical for infecting cells.
Using a technique called X-ray crystallography, which allows researchers to see the three-dimensional structure of the Spike protein at a resolution of individual atoms, as well as other biochemical approaches, James L. Daly of the University of Bristol and colleagues showed that this short sequence from Spike attached to neuropilin-1.
In experiments in the lab, the SARS-CoV-2 virus was able to infect fewer human cells that lacked neuropilin-1.
In cells with both the ACE2 and neuropilin-1 proteins, SARS-CoV-2 infection was greater compared to cells with either “doorway” alone.
Daly and colleagues showed that SARS-CoV-2 was able to infect fewer cells if they used a small molecule called EG00229 or antibodies to block the Spike protein’s access to neuropilin-1.