Abstract
Microbial pathogens exploit host nutrients to proliferate and cause disease. Intracellular pathogens, particularly those exclusively living in the phagosome such as Histoplasma capsulatum, must adapt and acquire nutrients within the nutrient-limited phagosomal environment. In this study, we investigated which host nutrients could be utilized by Histoplasma as carbon sources to proliferate within macrophages. Histoplasma yeasts can grow on hexoses and amino acids but not fatty acids as the carbon source in vitro Transcriptional analysis and metabolism profiling showed that Histoplasma yeasts downregulate glycolysis and fatty acid utilization but upregulate gluconeogenesis within macrophages. Depletion of glycolysis or fatty acid utilization pathways does not prevent Histoplasma growth within macrophages or impair 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, indicating that Histoplasma yeasts rely on catabolism of gluconeogenic substrates (e.g., amino acids) to proliferate within macrophages.IMPORTANCEHistoplasma 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 Histoplasma yeasts to be able to assimilate available carbon sources within the phagosome to meet their nutritional needs. In this study, we showed that Histoplasma yeasts do not utilize fatty acids or hexoses for growth within macrophages. Instead, Histoplasma 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.
Highlights
Microbial pathogens exploit host nutrients to proliferate and cause disease
To identify the carbon substrates that Histoplasma could potentially catabolize in the macrophage, we tested the ability of Histoplasma to grow in vitro on different organic compounds as the carbon source
The failure to grow on sucrose, despite the ability of Histoplasma to grow on the two monosaccharides that make up the disaccharide, likely results from its absence from the genome of the gene encoding Suc2
Summary
Microbial pathogens exploit host nutrients to proliferate and cause disease Intracellular pathogens, those exclusively living in the phagosome such as Histoplasma capsulatum, must adapt and acquire nutrients within the nutrient-limited phagosomal environment. We investigated which host nutrients could be utilized by Histoplasma as carbon sources to proliferate within macrophages. Histoplasma 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. Successful microbial pathogens must acquire nutrients from their host environment These necessary factors include major nutrients such as carbon, nitrogen, and sulfur for microbial growth and proliferation. The intracellular parasites Toxoplasma gondii and Leishmania major use catabolism of glucose and glucosamine, respectively, for proliferation within specialized parasitophorous vacuoles [5, 6]
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