A Histoplasma capsulatum lipid metabolic map identifies antifungal targets and virulence factors

Lipids play a fundamental role in fungal cell biology, being components of the cell membrane as well as targets of antifungal drugs. A deeper knowledge of lipid metabolism is key for developing new drugs and a better understanding of fungal pathogenesis. Here we built a comprehensive map of the Histoplasma capsulatum lipid metabolic pathway by integrating proteomic and lipidomic analyses. The map led to the identification of both the fatty acid desaturation and the sphingolipid biosynthesis pathways as targets for drug development. We also found that H. capsulatum produces analogs of platelet-activating factor, a potent regulator of the human immune response. The H. capsulatum platelet-activating factor analogs induced platelet aggregation and stimulated the production of the cytokines interleukin-10 and tumor necrosis factor-α by J774 macrophages. Overall, this lipid metabolic map revealed pathways that can be targeted for drug development, in addition to identifying a regulator of the host immune response.