Respiratory infections can be highly severe or even fatal for some people, while others may not experience such extreme outcomes. Researchers have made progress in understanding this phenomenon by identifying an early molecular factor linked to fatal illness. The enzyme Oleoyl-ACP-hydrolase (OLAH), which plays a role in fatty acid metabolism, has been shown to contribute to severe disease outcomes.
Respiratory infections can be severe, even fatal, for some individuals, but not for others. Researchers at St. Jude Children’s Research Hospital, the Peter Doherty Institute for Infection and Immunity, and other partners have gained new insight into this disparity by revealing an early molecular factor that can lead to fatal illness. Oleoyl-ACP-hydrolase (OLAH), an enzyme involved in fatty acid metabolism, has been found to drive severe disease outcomes, according to a study published today in Cell.
The crucial role of OLAH in the immune response has often been overlooked for several reasons, such as minimal expression in healthy tissues and challenges in obtaining data reflecting OLAH expression before and after infections. In this study, the researchers compiled years of collaborative research across various diseases to construct the extensive datasets necessary to comprehend how OLAH functions.
“OLAH has a direct influence on disease severity across multiple relevant viral infections,” said Jeremy Chase Crawford, PhD, from St. Jude’s Department of Host-Microbe Interactions, who is both a co-first and co-corresponding author. “We initially focused on avian influenza, but through collaboration, we were able to explore this biological mechanism in a much wider range of diseases.”
Transcriptomics highlights the key role of OLAH
Initial evidence identifying OLAH as a contributor to severe disease emerged from studies on avian A(H7N9) influenza. Transcriptomic analyses revealed a connection between OLAH expression and fatal outcomes in A(H7N9) infections shortly after hospital admission, with high levels of OLAH persisting in patients whose conditions worsened. Conversely, those who recovered had low OLAH levels throughout their hospital stay. This prompted researchers to broaden their collaborations to investigate OLAH expression in various infection cohorts and mouse models.
“We were creating transcriptomic datasets from different studies over years focused on distinct patient groups. It became apparent to us to examine OLAH, which led to remarkable associations across various diseases,” Crawford, a founding member of the St. Jude Center for Infectious Diseases Research, explained.
This research indicated that high levels of OLAH were present in patients hospitalized with severe cases of seasonal influenza, SARS-CoV-2, respiratory syncytial virus, and multisystem inflammatory syndrome in children, but not in those with mild illnesses. Furthermore, studies with mice that lacked OLAH showed that infections typically considered deadly could be survived.
The researchers also found that this effect was linked to altered lipid droplet behavior, diminished viral replication in macrophages, and inflammation triggered by the virus. Their investigation suggests that the inflammatory reactions and severe disease outcomes linked to OLAH are due to elevated levels of fatty acids produced by the enzyme, corroborated by earlier findings showing that viral infections worsen in cell lines with increased amounts of oleic or palmitic acid, both of which are byproducts of OLAH.
Potential implications for human health and disease
Co-corresponding and senior author Katherine Kedzierska, PhD, who leads the Human T cell Laboratory at the Doherty Institute, emphasized the study’s importance in enhancing our understanding of respiratory viruses and its potential implications for patient health.
“We are very optimistic about the possibility of the OLAH gene serving as a universal measure of disease severity for various respiratory infections,” Kedzierska stated.
“Imagine if doctors could predict whether a respiratory infection would turn life-threatening or if a patient would recover quickly. Our findings suggest that OLAH expression levels could serve as an advanced tool for assessing patient prognosis, providing clinicians with critical insights for early risk evaluation and personalized treatment plans,” she added.
In addition to clarifying OLAH’s role in severe respiratory viral diseases, the realization that OLAH expression occurs early in severe cases could position it as a useful biomarker for determining if patients require more intensive initial treatment. Also, experiments in mouse models indicated that supplementing oleic acid increased the replication of influenza in macrophages and enhanced their inflammatory response. This suggests that adjusting oleic acid levels might be a viable therapeutic strategy for treating these diseases.
“It took years of collaboration with basic scientists and clinicians from around the globe, each studying different infections and conditions, for the significant role of OLAH in immune responses to emerge. This marks just the beginning of our research into OLAH; much work remains in the field of infectious disease and other potential applications,” Crawford remarked.
