Metabolism of Gluconeogenic Substrates by an Intracellular Fungal Pathogen Circumvents Nutritional Limitations within Macrophages.

Microbial pathogens exploit host nutrients to proliferate and cause disease. Intracellular pathogens, particularly those exclusively living in the phagosome such as , must adapt and acquire nutrients within the nutrient-limited phagosomal environment. In this study, we investigated which host nutrients could be utilized by as carbon sources to proliferate within macrophages. yeasts can grow on hexoses and amino acids but not fatty acids as the carbon source Transcriptional analysis and metabolism profiling showed that yeasts downregulate glycolysis and fatty acid utilization but upregulate gluconeogenesis within macrophages. Depletion of glycolysis or fatty acid utilization pathways does not prevent growth within macrophages or impair virulence However, loss of function in Pck1, the enzyme catalyzing the first committed step of gluconeogenesis, impairs growth within macrophages and severely attenuates virulence , indicating that yeasts rely on catabolism of gluconeogenic substrates (e.g., amino acids) to proliferate within macrophages. is a primary human fungal pathogen that survives and proliferates within host immune cells, particularly within the macrophage phagosome compartment. The phagosome compartment is a nutrient-limited environment, requiring yeasts to be able to assimilate available carbon sources within the phagosome to meet their nutritional needs. In this study, we showed that yeasts do not utilize fatty acids or hexoses for growth within macrophages. Instead, yeasts consume gluconeogenic substrates to proliferate in macrophages. These findings reveal the phagosome composition from a nutrient standpoint and highlight essential metabolic pathways that are required for a phagosomal pathogen to proliferate in this intracellular environment.