IRE1α Is Associated with Host Lipid Biosynthesis During Human Coronavirus OC43 Infection

Research into the replication of human coronaviruses has surged, but much remains unknown regarding the host factors that influence disease. These viruses often activate cellular endoplasmic reticulum (ER) stress responses, benefiting from incompletely understood downstream effects. In this study, we investigated the role of the host ER stress response component, inositol-requiring enzyme 1 α (IRE1α), in regulating lipid metabolism during human coronavirus OC43 (HCoV-OC43) infection. We found IRE1α-dependent induction of lipogenesis-related genes, increased metabolic intermediates, and enhanced lipophilic membrane staining during infection. Inhibition of de novo fatty acid synthesis impaired HCoV-OC43 replication, while bypassing the first steps in de novo lipogenesis with supplementation of exogenous palmitate restored viral replication in the setting of IRE1α inhibition. Together, these results suggest that lipid metabolic remodeling is associated with IRE1α signaling during coronavirus infection and targeting these host pathways may represent a potential antiviral strategy.