Histoplasma relies on gluconeogenic substrates to circumvent nutritional limitations within macrophages
Microbial pathogens rely on exploiting host nutrients to proliferate during infection. Intracellular pathogens, particularly those exclusively living in the phagosome such as the primary pathogen Histoplasma capsulatum, must be able to assimilate available carbon sources within the phagosome to meet their nutritional needs. In this study, we investigated which host nutrients could be utilized by Histoplasma as the major carbon source to proliferate within macrophages. Histoplasma yeasts can grow on hexoses and amino acids but not fatty acids as the sole carbon source in vitro. Transcriptional analysis and metabolism profiling showed that Histoplasma yeasts down-regulate glycolysis and fatty acid utilization but up-regulate gluconeogenesis within macrophages. Depletion of glycolysis or fatty acid utilization pathways does not prevent Histoplasma growth within macrophages nor impairs virulence in vivo. However, loss of function in Pck1, the enzyme catalyzing the first committed step of gluconeogenesis, impairs Histoplasma growth within macrophages and severely attenuates virulence in vivo. Taken together, our data indicate that Histoplasma yeast catabolizes gluconeogenic substrates (e.g., amino acids) to proliferate within macrophages.