Researchers have discovered that the enzyme Oleoyl-ACP-hydrolase (OLAH) significantly affects the severity of respiratory viral infections, offering new hope for early risk assessment and personalized treatment strategies.
Researchers at St. Jude Children’s Research Hospital, the Peter Doherty Institute for Infection and Immunity and Fudan University, among others, have unveiled a critical piece in the puzzle of why some individuals experience severe, life-threatening respiratory infections while others do not. Published in the journal Cell, the study highlights the role of the enzyme Oleoyl-ACP-hydrolase (OLAH) in driving serious disease outcomes.
Respiratory viral infections, such as influenza and COVID-19, exact a heavy toll in terms of morbidity and mortality. The newly identified role of OLAH, an enzyme involved in fatty acid metabolism, could pave the way for innovative treatments and early risk assessments that save lives.
“OLAH directly impacts disease severity in multiple globally relevant, but distinct viral infections,” Jeremy Chase Crawford, co-first and co-corresponding author of the study and a leading figure in the St. Jude Department of Host-Microbe Interactions, said in a news release.
This discovery was born from an extensive collaborative effort spanning multiple years and various diseases. Initial clues were discovered during studies of avian A(H7N9) influenza, with transcriptomic analysis showing elevated OLAH levels in patients with fatal infections. This pattern persisted across different patient cohorts and diseases, including seasonal influenza, SARS-CoV-2 and respiratory syncytial virus.
“We were generating transcriptomic datasets from several different projects, through years of studying distinct patient cohorts. It occurred to us to look at OLAH, and that’s how we started to see these amazing associations across different diseases,” added Crawford, who also helped found the St. Jude Center for Infectious Diseases Research.
The research also included mouse models, where the absence of OLAH significantly increased survival rates in otherwise lethal infections. This was linked to differential lipid droplet dynamics, reduced viral replication in macrophages and modified inflammatory responses. The data suggest that OLAH-produced fatty acids, such as oleic acid, exacerbate viral infections.
Co-corresponding and senior author Katherine Kedzierska, a professor at the University of Melbourne and head of the Human T cell Laboratory at the Doherty Institute, underscored the significance of these findings.
“We’re really excited about the potential of the OLAH gene to serve as a universal indicator of disease severity across different respiratory infections,” she said in the news release. “Imagine if your doctor could predict whether your respiratory infection will become life-threatening or if you’ll recover rapidly? 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 personalized treatment strategies.”
The understanding of OLAH’s role could revolutionize clinical approaches by serving as a biomarker for severe respiratory infections. It may also open new therapeutic avenues, such as modulating oleic acid levels to improve patient outcomes.
Crawford emphasized the extensive international collaboration required to uncover OLAH’s role in immune response.
“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,” he added.
The study, supported by various international grants and institutions, marks a significant step in understanding and potentially mitigating the impact of severe respiratory viral diseases.