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With respiratory viral infections posing significant health threats, researchers and clinicians have long grappled with the mystery of why some individuals succumb to severe infections while others recover unscathed. 

In a study published in Cell and led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute), researchers revealed the critical role of a gene called OLAH in disease severity. Their findings show that highly elevated expression levels of OLAH were strongly associated with severe respiratory viral infections, while minimal OLAH expression was found in recovery and milder disease. 

The University of Melbourne’s Dr Brendon Chua, a viral and translational immunologist at the Doherty Institute, guided the innovative research and is a co-senior author of the paper. 

“Our first ‘aha’ moment occurred during our analysis of patients hospitalised with A(H7N9) influenza, where we discovered a consistent association between high expression levels of OLAH and fatal outcomes. Conversely, patients who recovered exhibited very low OLAH expression throughout their hospital stay,” said Dr Chua. 

“Further investigation using animal models and cell cultures revealed that OLAH is pivotal in driving life-threatening inflammation associated with respiratory viruses. What’s interesting is that we all have this gene, but its expression varies during the early phases of a respiratory infection, which is why some of us recover faster while others experience severe complications.” 

The researchers found elevated levels of OLAH in patients severely infected with seasonal influenza virus, SARS-CoV-2, respiratory syncytial virus (RSV) and in children experiencing multisystem inflammatory syndrome, a condition associated with COVID-19, but not in mild cases. 

The University of Melbourne’s Professor Katherine Kedzierska, Head of the Human T cell Laboratory at the Doherty Institute who has been leading this research since 2013, highlighted the research’s significance in advancing our understanding of respiratory viruses and its potential far-reaching impact on patients’ health. 

“We’re really excited about the potential of the OLAH gene to serve as a universal indicator of disease severity across different respiratory infections,” said Professor Kedzierska. 

“Imagine if your doctor could predict whether your respiratory infection will become life-threatening or if you'll recover quickly? Our findings suggest that OLAH expression levels could be used as a cutting-edge tool in assessing patients’ prognosis, empowering clinicians with crucial insights for early risk assessment and personalised treatment strategies.” 

This research is the result of a fruitful partnership between the Doherty Institute and Fudan University, China, established in 2014 to address global infectious diseases, and involved collaborations with numerous researchers worldwide, including from St Jude Children’s Research Hospital, USA. 

University of Melbourne Laureate Professor Sharon Lewin, Director of the Doherty Institute, commended the researchers for their potentially life-saving discovery. 

“I'm immensely proud of the groundbreaking work conducted by Professor Kedzierska and her team at the Doherty Institute in collaboration with colleagues globally, including Fudan University. This study, which has been 10 years in the making, represents a monumental effort, ultimately shaping the future of respiratory infection management,” said Professor Lewin. 

“This research provides invaluable insights that could profoundly impact clinical practice and the lives of people suffering with respiratory infections. I look forward to the day this novel method is available for use with patients.” 

The team is now working on developing OLAH-based diagnostic methods that can be deployed in clinics to screen hospitalised patients upon admission and differentiate between those who will recover and those who will face life-threatening outcomes. 

Highlighting the significance of this discovery, Dr Jeremy Chase Crawford from the St Jude Department of Host-Microbe Interactions and Center for Infectious Diseases Research, co-first author of the study, emphasised the potential for future research.

“It took years of working closely with basic scientists and clinicians, from across the world, all studying different infections and diseases, for OLAH’s important role in immune response to come to light. This is just the beginning of our exploration of OLAH; there is a lot more work to be done in infectious disease and other potential applications,” said Dr Crawford. 

Professor Kedzierska and her team will explore how OLAH can inform the development of therapeutic treatments for pathogens of pandemic potential, one of the foundational projects funded by the Cumming Global Centre for Pandemic Therapeutics. The Centre was established following a $250 million donation to the University of Melbourne by Mr Geoffrey Cumming – the largest philanthropic donation to medical research in Australia’s history.  

• Peer review: Jia XX, et al. High expression of oleoyl-ACP-hydrolase underpins life-threatening respiratory viral diseases. Cell (2024). DOI: https://doi.org/10.1016/j.cell.2024.07.026

• Funding: This study was funded by the National Health and Medical Research Council, Australia, China Scholarship Council-University of Melbourne Joint Scholarship, the National Institutes of Health and ALSAC, the fundraising and awareness organization of St Jude. 

• Collaboration: This study was a multi-institute collaboration between the Doherty Institute, Fudan University (China), St Jude Children's Research Hospital (USA), Bio21 Institute, Latrobe University, Boston Children's Hospital (USA) and Center for Influenza Disease and Emergence Responses (CIDER; USA).