Q&A: How Covid-19 hijacks human cells

Why is the molecular biology of viruses important?

I’ve always been interested in how cells are hijacked by viruses. When you look at a virus through a microscope, you can only see so much because they are really small compared to a cell. It is a bit like looking at a building from a satellite – you can’t see the people inside or how they open the doors to get in. I’m trying to understand how a virus opens the door to get inside the cell and take it over at a molecular level – what cellular proteins and processes are involved.

How did you end up working on Covid-19?

For several years I have been studying flu and a few other viruses like Zika and HIV-1 (the most common HIV virus). We have been finding that many viruses use the same doors to get into a cell, but open them in their own individual ways. When the genetic sequence of Sars-CoV-2 (the virus that causes Covid-19) was published in February, we immediately recognised part of the sequence that codes for the spike protein.

What is the spike protein?

The Sars-CoV-2 virus has all these spikes sticking up from the virus particle that make it look like a crown – that is whyit is called a coronavirus (corona is Latin for crown). These spikes are proteins that are like a hook on the outside of the virus particle, which allow it to recognise and bind to human proteins on the surface of cells. Without the spike protein, the virus would have no way of sticking to the surface of cells and infecting them.

The spike protein is also the ideal target for vaccines – both the Moderna and Pfizer/BioNTech vaccines target the spike protein – so understanding it helps to improve them.

What caught your eye about the Covid-19 spike protein?

The spike protein really differentiates this coronavirus from previous ones.We know about the ones that cause SARS or MERS. It’s got these specific, unique sequences at the molecular level that allow it to bind to proteins on the cell surface. At some point this (novel) coronavirus obtained a sequence in its spike protein that allows it to be cleaved in two by an enzyme found in its host (humans) called furin. We had seen this furin cleavage in other viruses such as in the H5N1 highly pathogenic avian flu virus, where it appears in the flu equivalent of the spike protein. Other pathogenic viruses also have furin cleavage sites on the proteins that bind to cells – HIV, Ebola and Crimean-Congo haemorrhagic fever virusall have them.

Why is this important?

The scientific community already knew that Sars-CoV–2 had at some point obtained the ability to bind with a greater affinity to a receptor protein (a type of protein on the surface of a cell) called ACE2 compared to the SARS coronavirus. But when the furin cleaves the spike protein, it exposes a new sequence which allows it to bind to another host cell protein and hijack its function. We identified that protein as neuropilin 1 and it could be this that makes Sars-CoV–2 so highly infectious in many organs.

‘I’m trying to understand how a virus opens the door to get inside the cell and take it over at a molecular level – what cellular proteins and processes are involved.’

-Dr Yohei Yamauchi, University of Bristol, UK

What does neuropilin 1 normally do in the body?

Neuropilin 1 is a receptor protein found on the surface of many cells that triggers the transportation of the molecules that bind to it inside the cell. It also allows molecules to be passed from cell to cell. In 3D tissue, that means something binding toneuropilin 1 on the top layer of cells could easily reach the middle layers of cells. 

Some people in cancer biology are very interested in it for this reason. If you can trigger neuropilin 1, you can increase the uptake of small drug molecules into otherwise solid tumours. 

How does this help the virus? 

This is still a hypothesis, but we think viruses able to trigger neuropilin 1 might be able to dig deeper into tissues without first having to replicate themselves in the upper layer of cells. That would be an amazing bypassing mechanism for a virus. 

Would that make it harder for the immune system to spot them too?

Exactly. And it would eventually mean the virus spreads quicker. It would help to give it this broad tropism (ability to infect many different organs and tissues)we are seeing in Covid-19 compared to the coronavirus that caused SARS, which doesn’t have that furin cleavage site. The current virus is able to cause neurological symptoms like loss of smell, and taste, it is causing myocarditis (inflammation of the heart) in some patients, as well as going to the lungs.

We think the CoV-2 virus might be using neuropilin 1 to facilitate trafficking into other types of cells by binding to cells on the surface of tissues that have neuropilin 1.

Can we use neuropilin 1 to find new treatments for Covid-19?

We are doing a follow up study on this, but we found that by interrupting the interaction between the viral spike protein and neuropilin 1 we can decrease infectivity in human cell cultures. Due to the intense study in cancer biology on neuropilin 1, there are already neuropilin 1-neutralising antibodies that have been in phase 2a clinical trials in the US against certain types of cancer. There is also a small molecule antagonist that competes with other molecules at the neuropilin 1 binding site. Those are already out there, so by fine tuning them and improving their affinity (ability to bind to neuropilin), we could produce some sort of drug that interrupts the interaction of the virus spike protein with neuropilin 1. It could be effective in reducing the severity of disease in patients.