Professor Phil Hansbro with Nicole Hansbro. Photo Toby Burrows.
Most people experience mild respiratory symptoms with COVID-19 but about one in 10 will progress to pneumonia and severe disease, says medical researcher Professor Phil Hansbro. The death rate is high for those who end up in intensive care.
“We need to target treatments to those who are most at risk of progressing to these more severe diseases,” says Prof Hansbro, who is leading a Sydney-based team undertaking high-security testing of potential treatments.
Prof Hansbro is an internationally recognised researcher in respiratory disease and Director of the Centenary UTS Centre for Inflammation – a joint venture between the University of Technology Sydney and the Centenary Institute studying the role of the body’s inflammatory process. At its best, inflammation is a helpful immune response to injury or infection, but it can also have a harmful role in diseases such as chronic obstructive pulmonary disease (COPD) and, now, COVID-19.
The most severe cases of COVID-19 are being driven by virally induced “hyperinflammation”, Prof Hansbro says. Inflammatory cells and inflammatory factors called cytokines propel this hyperinflammation, damaging the patient’s tissues while trying to get rid of the virus.
His team of researchers is trying to shine light on what the components of that hyperinflammation are, and testing and developing treatments that could dampen them down so people don't die from the sort of acute respiratory distress that has been seen in patients.
The researchers have access to high-level biocontainment laboratories at Centenary, an independent medical research institute in Sydney. One lab is being repurposed for the work on COVID-19, enabling the team to conduct SARS-CoV-2 infections of primary human respiratory cells collected from people’s airways or on special mice bred to carry the human receptor that’s the entry-way for COVID-19.
They will assess which treatments might be effective against COVID-19 and, just as importantly, which treatments might have damaging side-effects. Highly controlled comparative experiments between different treatments will aim to identify the therapies that are most effective and which should, therefore, be at the front of the queue for clinical trials in humans. With hundreds of pre-clinical trials under way around the world, the need to prioritise is high, says Prof Hansbro.
Interestingly, these inflammasomes are present at low levels in bats, which harbour these kinds of viruses but don't suffer from them.
— Professor Phil Hansbro
One path for investigation is the inflammasome, which is activated by infections and causes cytokine storms and hyperinflammation.
“Interestingly, these inflammasomes are present at low levels in bats, which harbour these kinds of viruses but don't suffer from them," Prof Hansbro says. “One of the things we're working on is an inhibitor of these inflammasomes.”
The team is also working on what is known as complement – a cascade of proteins that’s also induced in an inflammatory response, and in particular in acute respiratory distress. “We have inhibitors of complement that we’re also trying,” says Prof Hansbro. “We also have antibodies against a lot of these individual inflammatory factors that we're trying alone or in combination.”
Another pathway for investigation is whether it’s possible to block or inhibit the ACE-2 receptor that the virus binds to.
With potential anti-inflammatory approaches, a key question will be: if you give patients with a viral infection an anti-inflammatory, are you also suppressing the immune response you need to get rid of the virus?
Researchers have been finding treatments that are effective against these disorders and the question is whether they could be used also to combat COVID-19.
— Professor Phil Hansbro
Prof Hansbro, who has long worked to understand the mechanisms of respiratory diseases like COPD and asthma, as a pathway to therapies, says existing treatments being used for these populations of patients may hold some of the answers for COVID-19.
“Researchers have been finding treatments that are effective against these disorders and the question is whether they could be used also to combat COVID-19,” he says.
These treatments include things like metabolic modulators and hypoxia inhibitors, along with more standard therapies such as steroids and the antibiotic erythromycin, which has anti-inflammatory properties.
It’s been quite surprising that asthmatics don't seem to have been as susceptible to COVID-19 as at first feared, Prof Hansbro notes. “Is that because they’re taking steroids for their asthma? Is that suppressing the inflammatory response? That's an interesting avenue.”
An effective treatment response is likely to involve a combination of therapies, using both antivirals and anti-inflammatories, he says.
Timing of different treatments is likely to be important too. Patients might go on antivirals as soon as they see symptoms, then proceed to anti-inflammatories – perhaps in combination with the antivirals. The scientists will be able to compare different treatments to work out what treatments work at what stage of disease.
“We’re starting off broad and trying to find something that works, then as we do that our work will become more and more refined until we solve more and more of the problems,” Prof Hansbro says.
There are many possibilities, with many treatments being investigated around the world. “But we have the systems in place here to try to test their efficacy, both in human cells and animals – to see what’s effective, what may have deleterious effects, and what we might prioritise for clinical trials in humans.”
Report
Hsu, A.C., Starkey M.R., Hanish I., Hansbro, P. et al Targeting PI3K-p110α Suppresses Influenza Virus Infection in Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine. 2015;191(9):1012‐1023.
Research team
-
Chair of Inflammation, School of Life Sciences
Faculty and unit
- Faculty of Science
- Centre for Inflammation
Funded by
- University of Technology Sydney
- The Centenary Institute
