Discussion
inflammation
INFLAMMATION, VIRUS
Viruses are dependent on host metabolism to obtain macromolecules essential for their lifecycle. While metabolic interventions of host pathways offer promise, the current reliance on animal models and cell lines limits our ability to identify targets for intervention due to critical metabolic and genetic differences between animal models, cell lines, and patients. In this work, we utilized primary human cells and clinical samples to chart SARS-CoV-2 metabolic response, to identify metabolic targets that could rapidly translate to the treatment of severe COVID-19.Glycolysis is often upregulated to supply nucleotides for virus replication (Our study demonstrates coordinated changes in lipid metabolism, such as the upregulation of palmitoylation and cholesterol synthesis (Fibrates are a family of amphipathic carboxylic acids that are ligands of PPARα, known to up-regulate lipid oxidation and lower serum triglycerides (Our work shows that several structurally different ligands of PPARα have a similar anti-viral effect (One challenge in the investigation of host metabolic pathways in vitro is the difficulty to study lipid metabolism in proliferating cell lines and stem-cell-derived models (One challenge in the validation of our findings is that hamster models are unresponsive to fibrates (The clinical importance of understanding the role of lipid metabolism in COVID-19 is further emphasized by the negative response induced by thiazolidinediones (TZD) in our study. Thiazolidinediones are ligands of PPARγ that upregulate lipogenesis in certain tissues (To validate our findings, we carried out a prospective non-randomized interventional study of 15 severe hospitalized COVID-19 patients (NCT04661930). Severe COVID-19 patients treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care showed dramatic improvement in inflammation and faster recovery compared to patients admitted during the same period in neighboring hospitals and treated with the same standard of care (