Dissecting the regulatory circuits linking inflammation, infection, and metabolism to OLAH expression in myeloid cells 3791

Abstract Description OLAH (oleoyl-ACP hydrolase) is a rarely expressed enzyme involved in fatty acid biosynthesis, primarily the synthesis of oleic acid. We recently reported that upregulation of OLAH transcription during viral respiratory infection is an early and persistent biomarker of life-threatening illness from infections by seasonal and avian influenza viruses, SARS-CoV-2, and RSV (Jia, Crawford et al, Cell 2024). To dissect the molecular mechanisms underlying OLAH expression and to understand OLAH’s impact on downstream immune processes, we employed an integrative approach that combines systems analysis of human expression data with reductionist in vitro models of OLAH expression. Network analysis of human data identified OLAH as a potential mediator of inflammation and wound healing among specific myeloid subsets that traverse the respiratory tract and the peripheral immune system. In vitro experiments, for example utilizing the monocytic THP-1 cell line, demonstrated that OLAH expression can be induced by broad activators like Poly:IC and LPS, but not by Interferon gamma; however, upregulation of OLAH in the absence of exogenous cytokine stimulation also induced robust upregulation of interferon response genes like IFITM1. This work stands to distinguish the individual impacts of infection, inflammation, metabolism, and wound healing on OLAH expression in immune cells and the subsequent impact of OLAH expression on downstream immunological processes. Funding Sources Supported by ALSAC at St. Jude, NIH/NIAID R01-AI136514, and NIH/NCI grant P30CA021765. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)