Respiratory infections can be severe, even deadly, in some individuals, but not in others.
Scientists at St. Jude Children’s Research Hospital, the Peter Doherty Institute for Infection and Immunity and other collaborators have gained new understanding of why this is the case by uncovering an early molecular driver that underpins fatal disease. Oleoyl-ACP-hydrolase (OLAH) is an enzyme involved in fatty acid metabolism. A study, published in Cell, shows that OLAH drives severe disease outcomes.
The important role of OLAH in immune response has gone unrecognized for several reasons, including a lack of noticeable expression in healthy tissue, as well as the difficulty of obtaining datasets reflecting OLAH expression before and after infection. In this study, the researchers pieced together years of collaborative projects spanning multiple diseases to create the comprehensive datasets needed to understand how OLAH works.
The first clues pointing toward OLAH as a driver of lethal disease came from studies of avian A(H7N9) influenza. Transcriptomic analysis linked expression of OLAH with fatal A(H7N9) infection early after hospital admission, and OLAH levels remained high if a patient’s disease progressed lethally. Patients who recovered from their infection had low OLAH expression throughout their hospital stay. This finding led the researchers to expand their collaborations, looking for expression of OLAH in a variety of different cohorts of people who had experienced infections as well as in mouse models of disease.
Through this work, the investigators found high OLAH expression in patients hospitalized with life-threatening seasonal influenza, SARS-CoV-2, respiratory syntactical virus and multi-system inflammatory syndrome in children - but not during mild disease. Additional work with mouse models showed that in mice that were not expressing OLAH, infections that would otherwise be lethal were, in fact, survivable.
Additionally, the researchers found that this effect was accompanied by differential lipid droplet dynamics, reduced viral replication in macrophages and virus-induced inflammation. The work suggests that OLAH-mediated inflammatory responses and severe disease outcomes can be attributed to elevated levels of fatty acids produced by OLAH. This is supported by previous discoveries showing that viral infection in cell lines can be made worse by increased amounts of oleic or palmitic acid. The main product of OLAH is oleic acid.
In addition to defining the role of OLAH in severe respiratory viral disease, the understanding that OLAH expression begins early in severe disease may make it useful as a biomarker to determine if patients need more intense initial treatment.
