Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt

Abstract Immunometabolic changes induced by the fungal pathobiont Candida albicans drive complex responses in innate immune cells. However, whether and how C. albicans causes remodelling of oral epithelial cell metabolism is unclear. Here, we use in vitro experiments and patient biopsies to demonstrate that oral epithelial cells (OECs) undergo a transient metabolic reprogramming towards increased aerobic glycolysis and decreased activity of the tricarboxylic acid (TCA) cycle. Pharmacological inhibition of glycolysis shows that this pathway supports cytokine release by OECs whilst increased glycolysis exacerbates disease in a murine model of oropharyngeal candidiasis. Hexose supplementation disrupts epithelial cell responses both in vitro and in vivo, suggesting that increased aerobic glycolysis in OECs is detrimental. Transcriptomics data-based genome-scale metabolic modelling predicted changes in the TCA cycle and a novel role for glutamic-oxaloacetic aminotransferase 1 (GOT1) in response to C. albicans. Metabolomic and gene expression analyses indicated a partial shut-down of the TCA cycle, along with increased activity of pyruvate carboxylase and GOT1. Pharmacological targeting of GOT1 resulted in improved C. albicans infection outcomes. This study reveals a fundamental role for hexose metabolism, and identifies a novel GOT1-mediated TCA cycle shunt that drives OEC survival and immune responses during mucosal fungal infections.