Every fall, an asthma epidemic emerges in England, and when Stephen Holgate began his long research career, he was determined to understand what caused it. In the 1970s, allergy was a known trigger for asthma, and the evidence against air pollution was accumulating. Holgate was a medical registrar stationed at Salisbury and Southampton General Hospital, where he leveraged his expertise to explore possible infectious triggers.
He teamed up with David Tyrrel, director of the MRC Common Cold Unit in Salisbury, UK, who developed the first PCR test for the common cold coronavirus. It was a small part of a larger research puzzle that suggested that coronaviruses—along with influenza, parainfluenza, adenovirus and a rotating cast of less common respiratory viruses—appeared to drive worsening childhood asthma.
This seasonal stew of respiratory viruses underlies many hospital admissions for both infants and the elderly, and the COVID-19 pandemic has underscored that threat. But COVID-19 has also underscored the need for new and effective treatments for respiratory viral infections, and Holgate and the UK-based company he co-founded, Synairgen, are in hot pursuit.
At a December panel discussion hosted by Scientific American Custom Media and Synairgen, experts who worked in industry, academia and government discussed the urgent hunt for a versatile respiratory virus killer.
SACM:
How has COVID-19 changed how we think about severe viral respiratory disease?
Stephen Holgate
SARS-CoV-2 has shown us that the host response is very much the disease. The virus can exist as much as it likes, but the way the host responds to it creates the disease. If you have a rhinovirus and just get a common cold, that's one thing. But if it goes down into the bottom of your lungs and starts filling your lungs up with fluid because they can’t mount the necessary antiviral response, that's not so good.
SACM:
Most COVID-19 research focused on vaccines, which trigger the adaptive immune response, where the body learns to fight new foes. You’re interested in the innate immune response, the body’s front-line defenses. Why?
Stephen Holgate
People are starting to think more about the way the virus interacts with the host at the level of the epithelium, the tissue that lines all the internal and external surfaces of our bodies, and what equipment the virus has developed to subvert the innate immune response, before we even get to the adaptive immune response.
SACM:
How does asthma’s triplet of triggers—allergy, air pollution and viral infection—connect with the challenges of finding a broad-spectrum antiviral treatment for respiratory viral lung infections?
Stephen Holgate
We discovered that people with asthma and other lung diseases had reduced capacity to defend their lungs against common respiratory viruses. In a properly functioning system, a naturally occurring immune response triggered by the presence of [the signaling protein] interferon beta orchestrates the body’s antiviral response. Respiratory viruses can suppress interferon beta production. People with compromised immune systems, like those with asthma and chronic obstructive pulmonary disease (COPD), may be deficient in interferon beta production. There are no broad-spectrum antivirals currently available to overcome the assault on the body’s natural production of interferon beta, and treat the wide range of viral infections that put millions in the hospital each year. We need to focus on this, now more than ever.
SACM:
Can you take us through what’s known about interferons as immune activators?
Stephen Holgate
My colleagues and I discovered that a deficiency of interferon beta reduced the capacity to defend lungs against common respiratory viruses. Bats, for example, tolerate these and many other viruses without developing disease. These animals have an incredibly high basal expression of interferons.
What happens in those first few days with a respiratory virus, and maybe the first week or so, is all about what goes on in the lungs. This first steps—the passage of the virus into the epithelium, and then the subsequent interferon response,— are absolutely crucial in the propagation of the human disease as we now understand it. The same is true of influenza and RSV, and no doubt with these other respiratory viruses. Gradually, the bits of the jigsaw are coming together.
SACM:
How does this interferon beta antiviral response work?
Stephen Holgate
When a virus hits an epithelial cell, that cell makes a small amount of interferon beta. This is the background interferon that triggers the common interferon receptor on adjacent cells. There are a whole raft of these interferon-stimulated genes, which is why this is such an effective natural response. We learned from genome-wide association studies that there are defects in this interferon pathway in humans. If you've got a defect, these 300 or so genes don't get switched on as efficiently. Hence, the antiviral response is not as good as it should be. If we think about targeting the host, rather than just the virus, then we can think about replacing the missing interferon beta in the lung.
SACM:
How do you see this approach complementing other therapies and diagnostic tools?
Stephen Holgate
The first thing is viral diagnosis. I think point-of-care diagnostics have made the big step: when possible, understanding what virus you're dealing with is important, and then responding to that. With influenza and coronavirus, the rapidity with which these viruses cause lung damage means that you need to come in early with therapy. I think locally increasing levels of these primary interferons will help build resilience by limiting the proliferation of the virus and its subsequent downstream effects.
SACM:
How might these kinds of treatments help us combat the next pandemic?
Stephen Holgate
Antivirals were slow to come on the scene with COVID-19, and we had many false starts. Getting antivirals to be specific against the virus, but not cause toxicity, is not an easy task. Big pharmaceutical companies worked hard to do that. But we also need to switch our attention to strengthening the ability of the human body to resist the initial insults when they come, providing protection against a range of different viruses. One example of that is inhaled interferon. Another example is Vitamin D, which also increases resilience of the lung, and there may well be others. We do know that these agents directly strengthen the immune response. We need virus-agnostic treatments.
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