In mid-March, just after restrictions were put in place to slow the spread COVID-19, Dr Nigel Stevenson looked out the window of his Dublin apartment. "It was a beautiful, still evening, the sun was setting and there was no traffic on the roads. It was idyllic," he recalls. "Then I remembered why it was so quiet, and I thought... that damn virus."
Stevenson, who leads the Viral Immunology Lab in Trinity's Biomedical Sciences Institute, knows more about "that damn virus" than most. For more than a decade he has been working on disease-causing viruses, including HIV, Hepatitis C and, more recently, the coronaviruses SARS-CoV-1 (from the outbreak in the early 2000s) and MERS (from the outbreak in 2012). Now he has turned his lab's attention to the pandemic virus, SARS-CoV-2.
His interest? The biochemical dance between an invading virus and the human cell it seeks to hijack, and how understanding those interactions could help us design new therapies to stop infection.
“Some viruses, including the one that causes Covid-19, can hide from our immune systems early in the infection, and they can really get entrenched,” he explains. “By understanding how they do that, we could potentially bring the viruses out of hiding and help the immune system to clear the infection early on. That would lead to less disease.”
Interfering with interferon
When the SARS-CoV-2 virus – that causes Covid-19 – gets into our airways, it enters our cells and ejects its genetic material, co-opting the infected cell into making copies of the virus, which then go on to infect other cells.
One way our body defends us against this takeover is by releasing a substance called interferon, Stevenson explains. “Interferon is a really powerful defender, because it activates hundreds of other genes and proteins that effectively stop the virus in its tracks.”
But some viruses can interfere with the interferon response. Stevenson and his Trinity College Dublin colleague Prof Cliona O'Farrelly have previously shown the Hepatitis C virus can block a particular pathway of biochemical signals inside the cell, thereby stopping the cell from "telling" interferon to ramp up the molecular defences. "We could see that the virus degraded this biochemical pathway inside liver and immune cells," explains Stevenson. "And this blockade meant the body wasn't able to switch on its normal defences against the virus."
Stevenson has found other viruses use a similar mechanism to block responses to interferon, among them HIV. “We have been able to show that HIV-1 stops interferon too,” he says. “And we are looking at ways to prevent HIV-1 from doing that, and thereby restore the natural interferon response.”
Then, last year, in a case of spectacularly good timing, PhD student, Yamei Zhang, in Stevenson’s lab started to look at the effect of the original SARS and MERS coronaviruses on the Interferon response. “Our ongoing studies are showing that both the SARS-1 and MERS viruses use a conserved mechanism to block interferon,” Stevenson adds.
When Covid-19 became a serious public health concern, the researchers also turned their attention to SARS-CoV-2. Their analysis of the pandemic virus genome indicates that it too may use this process to suppress response to interferon, as it has a similar interferon-blocking code to the one Stevenson’s lab has studied in its coronavirus “cousins”.
“We are now studying this, because if this is one way through which SARS-CoV-2 evades our immune system, then it’s good news for our battle against this deadly virus,” says Stevenson. “Our lab is already working on ways to restore interferon’s biochemical pathway, so now we can apply these research discoveries to the pandemic virus too.”
Activation station
Another difficulty in Covid-19 is that when the immune system does respond to the virus later in the infection, it can over-respond in some people, damaging their lungs and other organs. Prof Andrew Bowie, also at Trinity, is trying to figure out the pathway to this response.
Like Stevenson, he has found himself in a good position to focus on SARS-CoV-2. “Last year, we started working with RNA viruses that affect the airways, trying to understand how these viruses trigger an immune response in lung cells,” Bowie says. “And now we can pivot that work to look at how the RNA virus SARS-CoV-2 does this.”
Bowie, along with O’Farrelly and Prof Luke O’Neill, are part of a European project called INITIATE, which explores how disease-causing viruses interact with human cells growing in the lab.
“We are looking at how the airway cells react to the viruses when they meet them, and the kind of inflammatory immune response that follows,” explains Bowie. “We and others have already discovered that viruses prompt a different kind of immune response in lung cells compared to the response we see to bacteria. Now we can look at how the inflammatory immune response gets switched on specifically in response to SARS-CoV-2, and what pathways are involved. It’s a good example of how answering a basic biological question will shed light about what is going on in patients who experience this kind of immune activation in Covid-19.”
Screen for medicines
Ultimately, we want the answers to those biological questions to translate into better ways to prevent or treat Covid-19. Dr Virginie Gautier at University College Dublin is marshalling her lab's resources to screen for such answers. Her expertise lies in host-virus interactions, and now she has re-oriented her lab to look at SARS-CoV-2.
“We are interested in the ways that cells respond biochemically to viruses, so that we can identify points of vulnerability that could be targeted by drugs,” explains Gautier, who is a principal investigator at the UCD Centre for Experimental Pathogen Host Research. “We also have a platform set up in the lab where we can apply specific drugs or other agents and see how that affects the virus when infecting the cells.”
With funding through the Health Research Board's national Covid-19 rapid response call, Gautier is now working with UCD Prof Paddy Mallon to screen for ways to block SARS-CoV-2 using that platform.
“We want to look at drugs that have already been approved for use in the clinic, so they could be repurposed for treating SARS-CoV-2 if they are effective, and we are looking at potential new agents against the virus too,” Gautier says.
Her lab is also helping to provide reagents for hospitals to test patient samples for SARS-CoV-2, she adds. “This pandemic needs us all to work together, to use the insights and systems we have developed for other viruses and focus on this one.”
