Discovering a molecular driver of lethal outcomes for viral respiratory disease 

What drives infections to become severe, perhaps even fatal, in some individuals but not in others is an area of infectious disease research that has been difficult to study. Collaborative research between St. Jude, the Peter Doherty Institute for Infection and Immunity, Harvard University, and other institutions, published in Cell, has shed light on the problem, revealing that oleoyl-ACP-hydrolase (OLAH), an enzyme involved in fatty acid biosynthesis, is a driver of severe disease outcomes. 

“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 the immune response to come to light,” said co-first and co-corresponding author Jeremy Chase Crawford, PhD, Department of Host-Microbe Interactions.

The lack of recognition for OLAH’s important role was due to difficulties in collecting unbiased datasets during severe disease. Because OLAH is rarely expressed, even in healthy tissue, scientists have long focused on panels of genes with presumed roles in disease. To overcome these barriers and better understand how OLAH works, the researchers assembled comprehensive datasets covering as many genes as possible from years of collaborative projects that examined multiple diseases. 

Researchers turned their attention to OLAH when transcriptomic analysis of blood from hospitalized patients infected with avian A(H7N9) influenza first showed a link between the expression of OLAH — present early after hospital admission and throughout disease progression — and fatal disease. This initial finding led Crawford to expand the datasets, examining the enzyme in different cohorts of individuals who experienced respiratory infections and in mouse models of disease. 

“We generated transcriptomic datasets from several 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,” explained Crawford, a founding member of the St. Jude Center for Infectious Diseases Research (CIDR). 

While subsequent studies of patients hospitalized for seasonal influenza, SARS-CoV-2, respiratory syntactical virus, and multi-system inflammatory syndrome in children found high expression of OLAH, mouse models demonstrated that a lack of OLAH expression correlated with infections that became survivable. The explanation for why lies in how OLAH produces elevated levels of fatty acids, namely oleic acid. These findings support previous research that showed viral infections in cell lines become worse when oleic or palmitic acid levels increase. 

The findings advance the understanding of respiratory viruses and have broad health implications. Not only could OLAH become an indicator of disease severity, but the knowledge that it is present shortly after symptom onset means it could be used as a biomarker to determine initial treatment responses.

“This is just the beginning of our exploration of OLAH,” Crawford said. “There is much more work to be done in infectious disease and other potential applications.”