Targeting Gasdermin E could offer clinicians the first real host-directed therapy to fight the deadly effects of severe influenza.
Australian scientists have discovered a protein that acts like a “self-destruct button” in the lungs during influenza infection, unlocking a potential new way to prevent severe illness and death from the virus.
Each year, influenza claims up to 650,000 lives globally and leads to significant hospitalisations, respiratory failure, and long-term complications.
Despite vaccination campaigns and antivirals, treatment options for severe flu remain limited – and resistance to existing drugs is increasing.
Latest data from Australia’s National Notifiable Disease Surveillance System (accessed 10 September), shows there have been 350,190 cases of laboratory confirmed influenza reported so far this year.
New South Wales is the standout hotspot (134,156 cases), followed by Victoria (79,473), Queensland (72,198), South Australia (24,498), Western Australia (24,329), the ACT (6792), Tasmania (5217) and the Northern Territory (3427).
In 2024 there were 365,591 cases in total reported – a number Australia is likely to surpass this year based on current trends.
Researchers led by Associate Professor Michelle Tate, of the Hudson Institute of Medical Research in Melbourne, and PhD student Sarah Rosli have shown that the protein Gasdermin E (GSDME) is a key driver of flu-related lung damage.
Their study, published in Cell Death & Disease, found that when GSDME is activated in lung epithelial cells, it forces the cells to burst open, releasing inflammatory signals that amplify tissue destruction and worsen illness.
“We found that a protein called Gasdermin E plays a major role in causing lung damage during influenza. By deleting this protein, we were able to reduce inflammation and improve survival,” said Professor Tate.
“We discovered that Gasdermin E acts like a ‘self-destruct’ button in lung epithelial cells during infection, causing them to burst and release inflammatory signals.”
Severe influenza continues to disproportionately affect older adults and people with weakened immune systems.
Current management relies on antivirals and supportive care, but once hyperinflammation sets in, few options exist.
By shifting the focus to host-targeted therapy, this research opens the door to medicines that may help patients recover faster while lowering mortality, said Professor Tate.
“Every year, thousands of people, especially adults 65+ and those with weakened immune systems, get seriously ill from the flu,” she said.
“Our findings could lead to new medicines that reduce lung damage and inflammation, helping people recover faster and lowering the risk of death from severe flu.”
She said the actions of this protein lead to more tissue damage and worsen illness.
“When we removed this protein, the lungs stayed healthier, and the flu was less severe. This opens up exciting possibilities for new treatments that help the body fight flu more effectively,” said Professor Tate.
This world-first study shows that a protein Gasdermin E is activated by multiple strains of the influenza virus and plays a central role in triggering epithelial cell death and uncontrolled inflammation.
“By blocking this pathway, we were able to reduce inflammation and viral replication, pointing to a new way to treat severe flu across different virus types,” Ms Rosli said.
Influenza spreads easily through droplets when an infected person coughs, sneezes or speaks. Symptoms such as fever, fatigue, muscle aches, cough and sore throat typically develop suddenly, setting flu apart from the common cold.
In Australia, peak transmission usually occurs between April and October. Annual vaccination remains the most effective defence, with vaccine composition updated each year to match circulating strains.
The discovery of Gasdermin E as a key culprit in influenza-related lung injury highlights a promising new path for treatment, the authors wrote.
Further translational research will determine whether inhibiting this protein can be developed into a safe and effective therapy for severe flu.
“There is an urgent unmet need for an effective host-targeted therapy for respiratory virus infections, particularly for a pathogen such as IAV [influenza A virus), which is capable of rapid mutation, and when existing antiviral drugs are mostly ineffective,” the researchers concluded.
“Given that hyperinflammation in the lungs resulting from a dysregulated host immune response is a major contributor to adverse clinical outcomes, inhibiting the GSDMD and/or GSDME pathways may be a potential therapeutic strategy that limits the progression and development of severe IAV-induced lung damage.
“Importantly, the development of targeted gasdermin inhibitors in the future would allow assessment of such a strategy in dampening pyroptotic cell death during severe IAV infection.”
