Gene expression linked to severity of respiratory viral infections

With respiratory viral infections posing significant health threats, clinicians have long grappled with the mystery of why some individuals succumb to severe infections while others recover unscathed. Now researchers have discovered that highly elevated expression levels of a gene called OLAH are strongly associated with severe respiratory viral infections, while minimal OLAH expression is found in recovery and milder disease.

This groundbreaking discovery is the result of a partnership between Melbourne’s Peter Doherty Institute for Infection and Immunity and Fudan University in China, established in 2014 to address global infectious diseases, and involved collaborations with numerous researchers worldwide. It has been published in the journal Cell.

“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,” said the Doherty Institute’s Dr Brendon Chua, a co-senior author on the study. “Conversely, patients who recovered exhibited very low OLAH expression throughout their hospital stay.

“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.

Professor Katherine Kedzierska, Head of the Human T cell Laboratory at the Doherty Institute, 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 Kedzierska, who has been leading this research since 2013.

“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.”

Kedzierska and her team are 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. They will also explore how OLAH can inform the development of therapeutic treatments for pathogens of pandemic potential.

Professor Sharon Lewin, Director of the Doherty Institute, said the research “provides invaluable insights that could profoundly impact clinical practice and the lives of people suffering with respiratory infections”. Co-first author Dr Jeremy Chase Crawford, from St. Jude Children’s Research Hospital in the USA, added that there is significant 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,” he said. “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.”

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